A pathway and network review on beta-adrenoceptor signalingand beta blockers in cardiac remodeling

Jihong Yang • Yufeng Liu • Xiaohui Fan •

Zheng Li • Yiyu Cheng

� Springer Science+Business Media New York 2013

Abstract It is well established that cardiac remodeling

plays a pivotal role in the development of heart failure, a

leading cause of death worldwide. Meanwhile, sympathetic

hyperactivity is an important factor in inducing cardiac

remodeling. Therefore, an in-depth understanding of beta-

adrenoceptor signaling pathways would help to find better

ways to reverse the adverse remodeling. Here, we reviewed

five pathways, namely mitogen-activated protein kinase

signaling, Gs–AC–cAMP signaling, Ca2?-calcineurin-

NFAT/CaMKII-HDACs signaling, PI3K signaling and

beta-3 adrenergic signaling, in cardiac remodeling. Fur-

thermore, we constructed a cardiac-remodeling-specific

regulatory network including miRNA, transcription factors

and target genes within the five pathways. Both experi-

mental and clinical studies have documented beneficial

effects of beta blockers in cardiac remodeling; neverthe-

less, different blockers show different extent of therapeutic

effect. Exploration of the underlying mechanisms could

help developing more effective drugs. Current evidence of

treatment effect of beta blockers in remodeling was also

reviewed based upon information from experimental data

and clinical trials. We further discussed the mechanism of

how beta blockers work and why some beta blockers are

more potent than others in treating cardiac remodeling

within the framework of cardiac remodeling network.

Keywords Beta-adrenoceptor signaling � Beta blocker �Cardiac remodeling � Network biology � Heart failure

Introduction

Cardiac remodeling was deemed as a determinant of clinical

course of heart failure. It comprises structural and functional

changes at different levels, such as molecular, cellular, tissue

and whole-organ levels [1]. It is well established that

hemodynamic load and neurohormonal activation are major

factors that have influences on cardiac remodeling. Changes

in hemodynamic load include reactive ventricular hyper-

trophy, progressive ventricular dilation, left ventricular wall

tension, stress increase and further dilation of the heart, while

neurohormonal activation is greatly related to increased

plasma and tissue levels of neurohormones, such as norepi-

nephrine, atrial natriuretic peptide (ANP), renin and aldo-

sterone [2]. These indicate that beta-adrenergic regulation

and renin–angiotensin–aldosterone system (RAAS) regula-

tion play crucial roles in the process of cardiac remodeling.

The neurohormonal activity of renin–angiotensin–aldoste-

rone axis and its molecular effects on the heart have been

reviewed by Gajarsa and Kloner [3]. It was clearly shown

which components are contained in the system, how bio-

logical agents, such as renin, angiotensin-converting enzyme

(ACE), angiotensin II and aldosterone, interact with other

components, effects of these components, and how phar-

maceutical agents, namely direct renin inhibitor, ACE

inhibitor, angiotensin II receptor blocker (ARB) and aldo-

sterone inhibitor, work in the system. In this review, we

focused on beta-adrenergic regulation, another important

influencing factor in the process of cardiac remodeling.

Although the exact process of cardiac remodeling is still

not clearly understood, cardiomyocyte lengthening is one

J. Yang � Y. Liu � X. Fan (&) � Y. Cheng

Pharmaceutical Informatics Institute, College of Pharmaceutical

Sciences, Zhejiang University, Hangzhou 310058, China

e-mail: fanxh@zju.edu.cn

Z. Li (&)

State Key Laboratory of Modern Chinese Medicine,

Tianjin University of Traditional Chinese Medicine,

Tianjin 300193, China

e-mail: lizheng1@gmail.com

123

Heart Fail Rev

DOI 10.1007/s10741-013-9417-4

of the important and certain processes [4, 5]. As myocyte

stretch, local norepinephrine activity increases leading to

activation of beta-adrenergic receptor (beta-AR). Beta-AR,

where the beta-adrenergic regulation starts, belongs to the

superfamily of G-protein-coupled receptors (GPCRs) or

seven transmembrane receptors and can be subdivided into

three subtypes, beta-1, beta-2 and beta-3 AR, with the

expression level of beta-1 AR being the highest, and beta-3

AR being the lowest in the heart [6]. Different subtypes can

mediate different signaling pathways [7]. Notably, some

are underlying the important cellular changes of remodel-

ing, such as myocyte hypertrophy, apoptosis and fibrosis

[1]. Therefore, a full understanding of these mechanisms

can broaden our understanding of finding ways to reverse

pathological remodeling and cardiac dysfunction. Beta

blocker directly targets the beta-adrenergic receptor and

has been shown to have beneficial effects on cardiac

remodeling [8, 9]. Better understanding of the anti-

remodeling mechanisms will benefit us in discovery and

development of more successful drugs. Thus, we will focus

on the beta-adrenoceptor pathways and networks that

mediate cardiac remodeling and mechanisms of beta

blockers in reversing cardiac remodeling.

Beta-adrenoceptor signaling in cardiac remodeling

Many mechanisms underlying cardiac remodeling when

induced by beta-AR stimulation have been revealed, such as

mitogen-activated protein kinase (MAPK) signaling, Gs–

AC–cAMP signaling, Ca2?-calcineurin-NFAT/CaMKII-

HDACs signaling, phosphatidylinositol 3-kinase (PI3K)

signaling, beta-3 adrenergic signaling, renin–angiotensin–

aldosterone system, interleukin-6/signal transducers and

activator of transcription 3 (IL-6/STAT3) signaling and

transforming growth factor (TGF)-beta signaling. In this

review, we will focus on the first five pathways and briefly

discuss other pathways.

MAPK signaling

Mitogen-activated protein kinases (MAPKs) are cytosolic

signaling proteins and consist of three subfamilies, namely

extracellular signal-regulated kinases (ERK1/2), c-jun

N-terminal kinases (JNKs) and p38 MAP kinase [10].

MAPK cascades are one of the most thoroughly studied

signal transduction systems, and it is well accepted that the

cascades are closely related to cardiac remodeling [10–12]. It

has been demonstrated that these proteins can be activated by

beta-AR stimulation both in vitro and in vivo [13–16]. In

response to beta-AR stimulation, nicotinamide adenine

dinucleotide phosphate (NADPH) oxidases can be activated

and promote the production of reactive oxygen species

(ROS). ROS is an important activator in cardiac MAPK

cascades and activates the guanosine triphosphate (GTP)

small G-protein (Ras), which induces Raf-1 kinase translo-

cation to plasma membrane. Raf-1 then phosphorylates

MEK proteins and in turn activates extracellular signal-

regulated kinases (ERKs), and functions as regulators in the

pathophysiological hypertrophy [10, 17, 18]. Li et al. [19]

recently demonstrated that RSK (downstream protein of

ERK) mediated the process via phosphorylation of a cardiac

transcriptional factor, GATA4, a critical regulator of cardiac

hypertrophy. In addition, excessive stimulation of beta-ARs

in the heart increases both cardiac Ang II production and

angiotensin-converting enzyme (ACE) activity [20]. Ang II

increases phospho-ERK1/2, thus leading to cardiac hyper-

trophy. Noma et al. [21] also showed that ERK can be acti-

vated by beta1-AR stimulation through beta-arrestin-

mediated transactivation of epidermal growth factor receptor

(EGFR). JNKs and p38 MAPK were suggested functioning

as mediators of cardiac remodeling. Some studies showed

that increased expression of MEK1/MEK7 (activator of

JNKs) and increased level of p38 MAPK phosphorylation

led to cardiac hypertrophy [22–24]. However, other studies

showed opposite conclusions [25–27]. In summary,

enhanced MAPK signaling was shown to promote hyper-

trophic cardiac remodeling, while the role of JNKs and p38

MAPK remains to be elucidated.

Gs–AC–cAMP signaling

Gs/AC/cAMP signaling cascade is a classic beta-AR sig-

naling pathway. Its harmful effects, such as cardiac

hypertrophy, fibrosis and dysfunction, have been revealed

in a series of experiments [28–31]. Both beta-1 AR and

beta-2 AR couple to Gs, which in turn activate adenylyl

cyclase (AC) and induce cAMP accumulation and protein

kinase A (PKA) activation. PKA phosphorylates cAMP-

response binding protein (CREB) and cAMP-response

element modulator (CREM). Lewin et al. [32] showed that

inactivation of CREM prevents beta-1 AR-overexpressing

mice from cardiomyocyte hypertrophy, fibrosis and left

ventricular dysfunction. However, another study showed

that CREB activation protected spontaneously hypertensive

rats (SHRs) from cardiac remodeling via inhibition of

cardiac apoptosis [33].

In addition, PKA plays a pivotal role in the circulation

of Ca2?, an important signaling molecule closely related to

cardiac remodeling in the cardiomyocyte. Activated PKA

phosphorylates sarcolemmal L-type Ca2? channels (LTCC)

and sarcoplasmic ryanodine receptors (RyR2) to increase

intracellular Ca2?. Phosphorylated phospholamban (PLB)

by PKA relieves its inhibition of sarcoplasmic reticulum

(SR) Ca2?-ATPase (SERCA2a), which triggers cytosolic

Ca2? reuptake into sarcoplasmic reticulum (SR) [34, 35].

Heart Fail Rev

123

PP1 inhibitor-1 (I-1) is also activated by PKA and inhibits

the effect of SERCA2a, resulting in amplification of

intracellular Ca2? [36–38]. Interestingly, I-1 can be deac-

tivated by calcineurin, thus constituting a connection

between two cardiac remodeling-related pathways, namely

cAMP-dependent pathway and Ca2?-calcineurin-NFAT

signaling pathway [39, 40].

Another recognized target for cAMP is Epac (exchange

protein directly activated by cAMP), which catalyzes the

exchange of GDP from GTP on small GTPase Rap [41–

44]. Expression of Epac1, one isoform of Epac, is increased

in hypertrophic myocardium, and silencing of the gene

blocks the hypertrophic effect of isoprenaline (ISO) in vitro

[45]. Epac1 is recruited at the plasma membrane by ISO

stimulation and activates H-Ras via Rap2B-PLC signaling.

It triggers the nuclear export of HADC4 (histone deace-

tylase 4) through CaMKII-dependent phosphorylation, with

the consequent activation of prohypertrophic transcription

factor MEF2 (myocyte enhancer factor 2) [46–48].

Ca2?-calcineurin-NFAT/CaMKII-HDACs signaling

Calcium is a signaling molecule necessary for activating

hypertrophic responses. The beta-AR-induced increase in

intracellular Ca2? is a complicated process. Under chronic

stimulation, beta-AR mediates PKA activation and sub-

sequent phosphorylation of LCCs and RyRs, which induces

rapid increase in intracellular Ca2? [34]. The increase in

intracellular Ca2? activates many downstream signaling

factors, including calcineurin- and calmodulin-dependent

protein kinase II (CaMKII), both of which play crucial

roles in corresponding hypertrophic pathways. However,

the source of Ca2? for activation of hypertrophic pathway

has been controversial for a long time. T-type Ca2?

channels (TTCC) [49], transient receptor potential channels

(TRPC) [50, 51] and L-type Ca2? channels (LTCC) [52–

54] were all previously reported as the entry. Chen et al.

[55] recently showed that Ca2? influx through the LTCC is

the major source of Ca2?, and cytosolic Ca2? activates

calcineurin-NFAT signaling [56], while sarcoplasmic

reticulum (SR) nuclear envelop Ca2? release activates

CaMKII/HDAC pathway. Calcineurin dephosphorylates its

downstream signaling factor NFAT, resulting in translo-

cation of NFAT proteins to the nucleus and activation of

many hypertrophic genes [57]. CaMKII-mediated phos-

phorylation of class II histone decatalases (HDACs),

especially HDAC4 and HDAC5, derepresses MEF2-med-

iated gene expression [58]. CaMKIId phosphorylates

HDAC4 preferentially compared with HDAC5, leading to

activation of hypertrophic genes [59].

In addition to the effect in hypertrophy, CaMKII-

induced apoptosis appears to play a role in contributing to

cardiac remodeling, and the process can be induced by a

variety of downstream mechanisms, such as the activation

of proapoptotic protease AP24 [60] and proapoptotic

factor Bcl10. Moreover, CaMKII can increase expression

of proapoptotic genes, downstream of MAPK kinase,

TAK1 [61] and ASK1 [62, 63]. With sustained beta1-AR

stimulation, CaMKII can be activated not only by

increased intracellular Ca2? that follows PKA-dependent

phosphorylation of Ca2? homeostatic proteins, but also

via the PKA-independent primary mitochondrial death

pathway [64, 65].

PI3K signaling

PI3K has been proven playing important roles in cell sur-

vival [66]. In cultured cardiomyocytes, beta-AR stimula-

tion increases PI3K activity [67, 68]. Both beta-1 AR and

beta-2 AR have been reported to transactivate PI3K in vitro

[69, 70] and in vivo [71].

PI3K alpha [72, 73] and PI3K gamma [72, 74] play

distinct roles in heart structure and function, and the latter

is also involved in pathological hypertrophy [74–76]. In a

recent study, Guo et al. [77] showed that the loss of PI3K

gamma led to enhanced cAMP generation resulting from a

loss of phosphodiesterase activity. The increased cAMP

levels activate phosphorylation of CREB, which could bind

to a cAMP-response element that is encoded in promoter

region of matrix metalloproteinase-2 (MMP2) and matrix

metalloproteinase-13 (MMP13) genes [78]. Thus, it leads

to increased MMP2 and MMP13 expression and activity.

Both of them are associated with cardiac remodeling, and

inhibition of them has shown favorable effects in pressure-

overload-induced cardiac remodeling [79]. In particular,

both MMP2 inhibition [80] and MMP2 gene deletion [81]

ameliorated hypertensive cardiac remodeling, and recent

research [82] also indicates that its polymorphisms may

modulate left ventricular remodeling.

In addition to two above-mentioned PI3 kinases, several

downstream factors of beta-AR-induced transactivation of

PI3K–Akt signaling pathway also play important roles in

the process of cardiac remodeling. Notably, increasing

evidences showed that beta-2 AR, but not beta-1 AR,

activates PI3K–Akt signaling pathway in a Gi-Gbc-

dependent manner [83–86]. Regulation of cell proliferation

and cellular protection against apoptosis in neonatal

cardiomyocytes are well-known result of activation of the

pathway [87, 88]. Akt phosphorylates the proapoptotic Bcl-

2 family member BAD [89, 90] and prevents BAD from

binding to Bcl-xl and Bcl-2, members of the Bcl-2 family

of proteins, thus releasing them for a cell survival response

[91]. Moreover, Akt also activates endothelial nitric oxide

synthase (eNOS) at Ser1177 and thereby promotes NO

production, which has favorable effects in cardiovascular

diseases [92].

Heart Fail Rev

123

Glycogen synthase kinase 3 (GSK-3) is another impor-

tant target of Akt and consists of two isoforms in human,

namely GSK-3a and GSK-3b [93]. The latter has been

shown inactivated by Akt under beta-adrenergic stimula-

tion in cardiac myocytes [67]. GSK-3b phosphorylates a

wide variety of cardiac transcriptional factors, such as

GATA4 [94], atrial natriuretic factors (ANF) [67] and

nuclear factors of activated cells (NFAT) [95], which leads

to induction of cardiac hypertrophy. The phosphorylation

of GSK-3a is also greatly increased under beta-AR stim-

ulation [71, 96], but its functions are far less clear than that

of GSK-3b. However, GSK-3a is becoming a focus in

recent years for its role in regulating cardiac remodeling

[96, 97]. Constitutive GSK-3a activity protects against

maladaptive remodeling secondary to chronic beta-AR

stimulation [96]. GSK-3a also negatively regulates hyper-

trophic growth [98, 99], and one of the key mechanisms is

dysfunction of mTORC1, which is a critical regulator in

cell growth [100]. In addition, Zhou et al. [98] found that

GSK-3a probably interacted with beta-adrenergic receptor/

G-protein-coupled receptor kinase/beta-arrestin and served

as a positive feedback loop to enhance beta-adrenergic

signaling, thereby preserving contractile function and left

ventricular (LV) function. Yet, in two earlier studies, they

have suggested that increased activity of GSK-3a induces

LV dysfunction in a transgenic and a knockin model,

respectively [99, 101]. The role of GSK-3a in cardiac

remodeling remains unclear, and more work is needed to

completely elucidate it.

The forkhead box family of transcription factors (FOXOs)

are also critical downstream elements of PI3K/Akt signaling

pathway. Zhang et al. [86] have demonstrated that phos-

phorylation level of both FOXO1 (Thr24) and FOXO3a

(Thr32, Ser318/321, Ser253) is significantly increased by

acute beta-AR stimulation for the first time. FOXOs have

been widely reported closely related to cardiac hypertrophy

and remodeling and treated as negative regulators [102–

106]. Moreover, the mechanism seems clear: The phos-

phorylated FOXOs is segregated in cytoplasm, thus results in

absence of nuclear active FOXOs, and the latter can promote

the transcription of atrogin-1 to inactivate cardiac tran-

scription factor NFAT via calcineurin.

Beta-3 adrenergic signaling

Beta-3 AR was first cloned by Emorine et al. (1989) [107]

and showed the role of mediating lipolysis [108] and ther-

mogenesis [109] in adipose tissue. However, many recent

reports indicated that beta-3 AR was also expressed in human

heart and closely related to cardiac remodeling. Whether

overexpression of beta-3 AR has favorable effects is still

controversial. Cheng et al. [110] reported the detrimental

effects and Zhao et al. [111] showed that changes in

expression coincide with ventricular remodeling. Some

other studies got opposite conclusions. For example, sig-

nificant exacerbation of pathologic remodeling was revealed

in mice lacking beta-3 AR [112], and chronic stimulation of

beta-3 AR was effective in reducing cardiac remodeling

[113]. Therefore, these reports regard activation of beta-3

AR as a cardioprotective factor, and negative inotropic

effects induced by the receptor could have favorable effects

in reversing cardiac remodeling [114].

It is well recognized that the negative inotropic effects

result from activation of nitric oxide synthase (NOS) sig-

naling through Gi proteins in cardiomyocytes [112, 113,

115, 116]. The synthesized nitric oxide (NO) binds to and

activates NO–guanylyl cyclase (NO–GC) [117], and sub-

sequent activation of NO–GC increases conversion of GTP

to cGMP, which could target many cellular proteins [118],

such as cGMP-dependent protein kinases (PKGs), cGMP-

gated cation channels and cyclic nucleotide phosphodies-

terases (PDEs). cGMP-dependent protein kinase I (PKGI)

isozymes play a pivotal role in mediating major effects

induced by NO–cGMP signaling [119, 120]. Its activation

has been shown to induce negative inotropic action, and the

proposed mechanism, action through inhibition of LTCC,

has been verified from different aspects [121–123].

Nitric oxide production is a key step in nitric oxide

synthase signaling, and both endothelial nitric oxide syn-

thase (eNOS) and neuronal nitric oxide synthase (nNOS)

are involved in the process. However, the primary isoform

participating in beta3-induced negative inotropic action has

been an important topic for a long time [113, 115, 116,

124, 125]. Endothelial NOS has been previously suggested

as the one that is solely responsible for beta3-induced

negative inotropy. However, in the study of Napp et al.

[126], NO-dependent negative inotropic effect was still

observed even though the eNOS-derived NO is decreased.

Thus, the role of eNOS as primary isoform is challenged.

Until recently, a recent study [113] made a clear elucida-

tion of the above-mentioned paradox. The activity of eNOS

can be activated by phosphorylation at Ser1177 and

deactivated by phosphorylation at Ser114 [127–129], and

eNOS is deactivated by an increase in Ser114 phosphory-

lation and a decrease in Ser1177 phosphorylation under

beta-3 AR stimulation. Furthermore, BRL (a beta-3 ago-

nist) treatment has no effect on eNOS recoupling. Hence,

eNOS is not the sole pathway for beta-3 AR. On the other

hand, nNOS protein expression is upregulated by beta-3

AR stimulation and attributes to maintaining equilibrium

of myocardial NO and reactive oxygen species (ROS)

production. Moreover, nNOS-/- mice developed more

severe LV remodeling. Therefore, nNOS is supported to be

the primary downstream NOS isoform participating in

beta-3 induced negative inotropy.

Heart Fail Rev

123

Extensive efforts have been made to better understand

the relationship between beta-3 AR signaling and cardiac

remodeling, but few studies have illustrated precise

mechanisms. Due to limited knowledge about the beta-3

AR signaling, whether activation of beta-3 AR is favorable

requires further studies.

Other signaling pathways

In addition to the above-mentioned five signaling path-

ways, other signaling pathways, such as RAAS, IL-6/

STAT3 signaling and TGF-b signaling, are also induced by

beta-AR activation and take part in the process of cardiac

remodeling. Under stimulation, expression of Ang II [20],

IL-6 [130] and TGF-b [131], the key regulators of these

pathways, is increased. Thereafter, (1) increased Ang II

levels could lead to cardiac hypertrophy in vitro and in vivo

[132–134]; (2) both IL-6 and Ang II could activate STAT3,

which acts as a transcriptional factor, thus promoting car-

diac hypertrophy [135]; and (3) overexpression of TGF-b

has also been demonstrated to lead to fibrosis and hyper-

trophy in transgenic mice [136]. All of these pathways are

closely related to cardiac remodeling.

Taken together, beta-adrenergic regulation plays an

important role in the pathogenesis of cardiac remodeling.

In particular, some biological molecules, such as SER-

CA2a, ERK, CaMKII, GSK-3a, GSK-3b, PKGI, MMP2,

STAT3 and TGF-b, could be potential targets for future

therapeutic approaches in the setting of cardiac remodel-

ing. A summary of the pathways involved in cardiac

remodeling can be found in Fig. 1.

Systems network of cardiac remodeling

To get a more systematic perspective of cardiac remodeling

process, we further built a regulatory network specific to

cardiac remodeling. We collected miRNAs and TFs that

have been reported involved in cardiac remodeling, and then

identified target genes of miRNAs and TFs from miRTar-

Base (Release 3.5, http://mirtarbase.mbc.nctu.edu.tw/) [137]

Fig. 1 Five beta-adrenoceptor signaling pathways mediated cardiac

remodeling. Different colors represent different signaling pathways.

Red Gs–AC–cAMP signaling; orange Ca2?-calcineurin-NFAT/

CaMKII-HDACs signaling; green MAPK signaling; blue Beta3-

adrenergic signaling; black PI3K signaling. Detailed information is

discussed in the text

Heart Fail Rev

123

and TFactS (Version 2, Sign-Sensitive catalogue, http://www.

tfacts.org/TFactS-new/TFactS-v2/index1.html) [138]. In

addition, we collected gene sets of the five discussed pathways

based on literature and confined connections between miR-

NA-target gene and TF-target gene via the collected gene sets.

Combined with protein–protein interaction of HPRD database

(http://hprd.org/) [139], a regulatory network was built based

upon regulatory interactions between miRNA and genes, and

protein interactions. The network contains 192 nodes and 438

edges (see Fig. 2, data available in supplementary files).

From the network, we can make a systematic investiga-

tion of miRNAs and TFs that are involved in pathways (see

Table 1). Taking the function of TFs and miRNAs into

account, it will benefit us to better understand the role of

these pathways in cardiac remodeling. Different pathways

may be involved in the same biological process, and this

triggers people to find out whether there exist some common

regulators. miRNAs, which have been seen as master regu-

lators of cellular processes [140], may regulate a series of

pathways and result in the same phenotype. miR-21, miR-

34a, miR-20a, miR-17 and miR-29a are common miRNAs

between PI3K signaling and MAPK signaling via analysis of

the network. miR-21 could target PTEN, leading to activa-

tion of ERK1/2 and AKT signaling pathway that follows

increased expression of HIF-1a and VEGF, and promotes

angiogenesis [141]. In addition, miR-34a has been proven as

a regulator of cellular responses to growth factor signaling

and dampens the proliferative and prosurvival effects path-

ways mediated by ERK and AKT [142].

The network also provided us a platform to view the

pathways in a more relevant context. Taking ‘‘PI3K sig-

naling,’’ for example, the relevant factors such as miR-195,

miR-181b, CREB and FOXO3 are involved in regulation

of cardiac myocyte hypertrophy, upregulation of miR-20a

and miR-21 is reported to inhibit apoptosis, members of

miR-29 family are involved in regulating extracellular

matrix, miR-126 and c-Myc are involved in regulating

cardiac angiogenesis, and activation of STAT3 can con-

tribute to improved LV function by inhibiting fibrosis. All

these above-mentioned biological processes regulated by

microRNAs and TFs are important in the process of

remodeling. Thus, it also indicates that PI3K signaling

plays roles in different stages of cardiac remodeling.

Beta blocker in cardiac remodeling

Based on the study of mechanisms of remodeling, various

types of drugs can be used for inhibiting or reversing

remodeling, such as ACE inhibitors, angiotensin II type I

receptor (AT1R) blockers (ARBs), beta blockers and

mineralocorticoid receptor antagonists (MRAs) [143]. Beta

blockers are widely used in hypertension and ischemia

heart disease for negative inotropic effect clinically, and

the first clinically significant beta blockers are invented by

Sir James Whyte Black. However, beta blockers were not

used for the treatment of cardiac remodeling and heart

failure initially, but considered contraindicated in patients

with chronic heart failure owing to their negative inotropic

action on myocardial contractility [144]. With decades of

research, understanding of pathogenesis of cardiac

remodeling is no longer confined to systolic dysfunction,

but also includes neuroendocrine abnormalities. Thus, beta

blockers are introduced as therapeutic agents of cardiac

remodeling due to its capability to inhibit neurohormonal

activation induced by beta-AR stimulation.

Clinical trials

Clinical trials on studying the beta blockers’ impacts have

been carried out for years. Several trials showed that some

beta blockers have effects on end-systolic/diastolic volume

decreasing or ejection fraction improvement (Table 2),

which are the most convincing measures to assess remod-

eling [1].

In all the above-mentioned beta blockers, only biso-

prolol, metoprolol (succinate formula) and carvedilol were

approved by FDA for use in heart failure treatment. Biso-

prolol, a selective beta1 adrenergic receptor blocker, has

significant effects on reducing mortality of patients in New

York Heart Association (NYHA) class III or IV [145]. In

CIBIS prognostic improvement study, bisoprolol treatment

improves fractional shortening, decreased end-diastolic

pressure and end-diastolic diameter, which refer to an

impact on end-diastolic volume [146]. This effect has also

been demonstrated in another trial with long-term treat-

ment of bisoprolol [147]. Metoprolol, same as bisoprolol,

also a selective beta-1 adrenergic receptor blocker, shows a

significant improvement of ejection fraction in MDC [148],

MRIF-HF [149] and a recent trial of chronic degeneration

mitral regulation [150]. End-systolic pressure was observed

to increase in MDC or decrease less than placebo in MRIF-

HF; however, this phenomenon has not been observed in

the trial investigated by Ahmed et al. [150]. Even so,

metoprolol treatment does bring on ejection fraction

improvement in varying patients and gets better remodel-

ing protection effects than bisoprolol. Carvedilol, an

antagonist for beta-1/2 and alpha 1 adrenergic receptors,

has a strong impact on improving left ventricular function.

It improves ESV, EDV and EF in several trials [151–155].

Moreover, carvedilol also improves another measure to

assess remodeling, such as LV mass and LV geometry

[156]. Carvedilol shows an extraordinary property on

protection for preventing adverse remodeling.

These clinical trails provided us direct evidence for beta

blockers to treat cardiac remodeling based on monitoring

Heart Fail Rev

123

of physiological measurements. More importantly, there

are a lot of cellular mechanisms underlying these clinical

traits, and exploration of these mechanisms could enable us

to discover and develop better therapeutic agents targeting

beta-AR signaling pathways. Although mechanisms of beta

blockers for preventing remodeling are not fully

understood, based on our present knowledge, Ca2? han-

dling exhibits a significant role, and many other mecha-

nisms related to beta-adrenoceptor pathways are also

involved. Moreover, we also discuss the influence of

receptor affinity and subtype selectivity on the treatment of

remodeling.

Fig. 2 A network of cardiac remodeling. miRNAs and TFs involved

in cardiac remodeling were collected from literatures, and their

targets were identified from miRTarBase (release 3.5) [136] and

TFactS (version 2, sign-sensitive catalogue) [137]. We collected gene

sets of the five discussed pathways based on literature and confined

connections of miRNA-target gene and TF-target gene via the

collected gene set. Combined with protein–protein interaction of

HPRD database [138], a regulatory network was built based upon

regulatory interactions between miRNA and genes, and protein

interactions. The network contains 192 nodes and 438 edges

Heart Fail Rev

123

Ca2? handling

Ca2? handling has been reviewed in the beta-AR-mediated

pathways and shows close association with pathological

remodeling. Lots of beta blockers, such as carvedilol, meto-

prolol, atenolol and propranolol, have been shown to prevent

the development of cardiac remodeling in different experi-

ments. These drugs share a similar mechanism involved in the

regulation of Ca2? handling proteins and channels. In a canine

model, low-dose propranolol restores RyR conformational

change and prevents Ca2? leak from RyR, thus resulting in an

attenuation of intracellular Ca2? [157]. Beta-AR blockade

with carvedilol, metoprolol and atenolol improves Ca2?

release channel function via RyR in patients with heart failure

to induce reverse remodeling [158]. Carvedilol and meto-

prolol also induce improvement of SERCA expression to

increase uptake of intracellular Ca2? [159]. In a genetic model

characterized by sympathetic hyperactivity-induced HF

(a2A/a2C-ARKO mice), carvedilol and metoprolol lead to

comparable treatment effect in cardiac remodeling. However,

metoprolol preferentially improved cardiomyocyte Ca2?

transient, while carvedilol inhibits Ca2? overload-induced

augmentation of mitochondrial oxygen consumption and

keeps the balance of global myocardial redox [160].

Other mechanisms

In addition to Ca2? handling, a lot of mechanisms are pro-

posed based on experimental studies. Metoprolol selectively

decreases myocardial expression of Bcl-xs, reducing the

Bcl-xs/xl and Bcl-xs/Bcl-2 ratio, thereby inhibiting apopto-

sis and favoring cell survival [161]. Nebivolol induces a

reduction in oxidative stress by reducing myocardial

NADPH oxidase activity, promotion of nitric oxide bio-

availability by activation of eNOS and increased NO bio-

synthesis [162]. Propranolol prevents the upregulation of

MMPs, whereas MMP inhibition reduces cardiac remodel-

ing [77]. To note, these proteins, such as Bcl-2, NADPH

oxidase, eNOS and MMPs, have been reviewed in the study

to play pivotal roles in beta-adrenoceptor pathways that

mediate cardiac remodeling. Thus, it is very likely that beta-

AR antagonists block these pathways via inhibition of beta-

AR and then prevent cardiac remodeling. Moreover,

monocyte chemoattractant protein-1 (MCP-1), matrix

metalloproteinases (MMPs) and their tissue inhibitors

(TIMPs) play a critical role in early phase of LV remodeling

following acute myocardial infarction and serve as early

markers. Carvedilol shows greater anti-remodeling activities

than metoprolol in a porcine ischemia/reperfusion model for

exerting much stronger effect on these markers [163]. This

may partially be responsible for higher treatment effect of

carvedilol than metoprolol in remodeling.

Affinity and receptor subtypes selectivity

Affinity reflects the binding capability of beta blockers to

beta-AR and largely determines the efficacy of beta

Table 1 Transcription factors, miRNAs and its target gene within

pathways

miRNAs related

with the pathway

Target gene

of miRNAs

in pathway

TF related

with the

pathway

Ca2?-calcineurin-NFAT/CaMKII-HDACs signaling

miR-1 CALM3, CALM2,

HDAC4

MEF2A, B, C,

D

Gs-AC-cAMP

signaling

miR-30a PPP3CA, ATP2A2 CREB1

NFKB1

NFATC2

Beta3-adrenergic signaling

miR-155 PDE3A SP1

PI3K signaling

miR-195 BCL2 CTNNB1

miR-20a BCL2 SP1

miR-17 BCL2 MYC

miR-181b BCL2 FOXO4

miR-21 BCL2 CREB1

miR-29c BCL2 FOXO3

miR-29b BCL2, MMP2 STAT3

miR-29a PI3KR1, BCL2 TP53

miR-149* AKT1 CEBPA

miR-126 PI3KR2 NFKB1

miR-34b* BCL2 FOXO1

miR-34a BCL2

MAPK signaling

miR-20a MAPK9, MAP3K12 CTNNB1

miR-17 MAPK9, MAP3K12 SP1

miR-24 MAPK14, TGFB1 MEF2D

miR-21 EGFR GATA4

miR-214 MAPK8, MAP2K3 FOXO1

miR-1 EGFR JUN

miR-29a TFGB3 MEF2A

miR-93 MAPK9 E2F1

miR-148a RPS6KA5 CREB1

miR-34a MAP2K1 STAT3

NFATC3

TP53

NFATC1

NFATC4

NFKB1

MEF2C

The asterisk following a name indicates a miRNA with lower expression

level relative to the other one derived from the opposite arm of a hairpin

Heart Fail Rev

123

blockers. Atenolol has been reported to be inferior to

metoprolol in improving LV function and preventing

ventricular remodeling in dogs with heart failure. EF

increase and ESV decrease are more significant in meto-

prolol-treated dogs than that of atenolol (EF 6.0 ± 0.86 vs.

0.8 ± 0.85 %, P \ 0.05; ESV -4.3 ± 0.81 vs. -

1 ± 0.52 ml, P \ 0.05) [164]. Carvedilol has been shown

to exert much stronger effect on inhibiting remodeling

from both experimental and clinical data. The result coin-

cides with the power of affinity of beta blockers (carvedi-

lol [ metoprolol [ atenolol, see Table 3). In addition, the

expression ratio of beta-1 AR versus beta-2 AR is 77:23 in

non-failing heart, while in the failing ventricle, beta-1 AR

is selectively downregulated and the ratio is 60:38 [165].

The relative content of beta-2 AR and beta-3 AR is

increased, thus facilitating drugs with higher selectivity of

beta-2 AR or beta-3 AR to exert favorable effects. The

affinity of metoprolol to beta-1 AR is little lower than

bisoprolol; however, as we have mentioned before, meto-

prolol gets better ejection fraction improvement compared

with bisoprolol. This may be explained by the higher

selectivity of beta-2 AR of metoprolol (see Table 3) [166].

In addition, carvedilol has been shown to be more effective

than metoprolol on attenuating ventricular remodeling after

heart failure, which may partially owing to higher binding

capacity of carvedilol to beta-3 AR in the failing ventric-

ular (see Table 3), thus contributing to inhibition of beta-3

AR expression [111].

Beta blockers and miRNAs

Few researches have revealed effects of beta blockers on

miRNAs in the process of cardiac remodeling; however,

some microarray studies have shown that beta blockers

altered miRNA expression profile and reversed expression

of some dysregulated miRNAs in this process [167, 168].

Moreover, Lu et al. [169] have explored the mechanism of

beta blockers on regulating the level of miRNA and proved

that propranolol produces beneficial effects via downreg-

ulation of miR-1, which contributes to ischemic ar-

rhythmogenesis. More interestingly, Ye et al. [170] have

recently compared the effects of nebivolol and atenolol in

salt-sensitive hypertensive rats and found that nebivolol

was more effective in attenuating cardiac remodeling than

atenolol, which was related to the unique effect of nebiv-

olol on miR-27a and miR-29a. Within the cardiac remod-

eling network, we can find that the targets of miR-27a and

miR-29a are FOXO1, BCL2, PIK3R1 and TGFB3 and they

located mainly in the beta-2 AR pathway (see Fig. 1).

Thus, it led us to reason that the effects of nebivolol might

be coming from its effects on beta-2 AR pathway.

Although nebivolol is universally acknowledged as a

highly selectively beta-1 adrenoceptor antagonist, it owns

some special pharmacological properties different from

other beta-1 adrenoceptor blockers. The clinically used

nebivolol is a racemate mixture of D- and L-enantiomers,

and the former has shown the ability to activate beta-2 AR

Table 2 Effect of beta blockers on end-systolic/diastolic volume and ejection fraction in trials (EDV/ESV/EF data contained trials only)

Investigator Year Beta

blocker

Placebo Drug Decreased

EDV

Decreased

ESV

Improved

LV EF

other

The CIBIS investigators [172] 1997 Bisoprolol 320 321 9(ESD) H(ESD) 9 LV FS increased

Beta blocker evaluation of

survival trial, investigators [173]

2001 Bucindolol 1,354 1,354 9 9 9

Colucci and colleagues [174] 1996 Carvedilol 134 232 H

Australia/New Zealand Heart

Failure Research Collaborative

Group [152]

1997 Carvedilol 207 208 H H H

Basu et al. [153] 1997 Carvedilol 72 72 H H H

Lowes et al. [155] 1999 Carvedilol 24 36 H LV mass and wall

thickness decrease,

geometry improves

Leonetti Luparini et al. [154] 1999 Carvedilol 20 20 H

Waagstein et al. [148] 1993 Metoprolol 189 194 H

MERIT-HF Study Group [149] 1999 Metoprolol 1,990 2,001 H

Ahmed et al. [150] 2012 Metoprolol 19 19 9 9 H

The SENIORS investigators [175] 2009 Nebivolol 1,058 1,053 9 H(ESD) H LV FS increased

ESV = end-systolic volume; EDV = end-diastolic volume; ESD = end-systolic volume; EDD = end-diastolic volume; LV = left

ventricular;9 = not significant result; H = significant result; blank means not mention; we consider ESD/EDD as alternative information of

ESV/EDV, but put it in brace

Heart Fail Rev

123

in a physiological model [171], thus providing a direct

evidence for nebivolol that can affect beta-2 AR pathway.

In addition, Ceron et al. [176] have just shown that this

agent could decrease vascular remodeling via attenuating

prooxidant and profibrotic mechanisms involving TGFband MMP2; this coincides with our aforementioned ana-

lysis of cardiac remodeling network. Taken together, these

efforts suggested that it is meaningful to explore the action

mechanism of drug and reasons for efficacy difference in a

systems regulatory network.

Conclusions

Cardiac remodeling is regulated by a very complicated net-

work of signaling molecules, genes, transcription factors and

miRNAs. Here, we reviewed five main pathways and its

regulatory network. Several beta-adrenoceptor signaling

pathways induced by beta activation are closely associated

with the cellular changes of remodeling. In general, these

activated pathways would induce adverse remodeling, while

some pathways, such as PI3K signaling and beta-3 signaling,

could be cardioprotective by promoting cell survival and

maintaining equilibrium of myocardial NO and ROS pro-

duction. Moreover, some molecular effectors in these path-

ways have shown the potential to be future therapeutic targets

for the treatment of cardiac remodeling. Meanwhile, beta

blockers, beta-adrenergic-receptor-targeted agents, show

outstanding benefits on remodeling. By studying the experi-

mental and clinical data, we summarize partial mechanisms

and the reason resulting in difference in treatment effects. In

summary, a comprehensive review of beta-AR signaling and

mechanisms of beta blocker in the treatment of remodeling

would help in disease therapy and drug development.

Acknowledgments This work was financially supported by the

National Basic Research Program of China (973 Program, No.

2012CB518405) and the Natural Science Foundation of China (No.

81373893).

Conflict of interests The authors declare that they have no com-

peting interests.

References

1. Cohn JN, Ferrari R, Sharpe N (2000) Cardiac remodeling—

concepts and clinical implications: a consensus paper from an

international forum on cardiac remodeling. Behalf of an inter-

national forum on cardiac remodeling. J Am Coll Cardiol

35:569–582

2. Vantrimpont P, Rouleau JL, Ciampi A, Harel F, de Champlain J,

Bichet D, Moye LA, Pfeffer M (1998) Two-year time course and

significance of neurohumoral activation in the Survival and Ven-

tricular Enlargement (SAVE) Study. Eur Heart J 19:1552–1563

3. Gajarsa JJ, Kloner RA (2011) Left ventricular remodeling in the

post-infarction heart: a review of cellular, molecular mecha-

nisms, and therapeutic modalities. Heart Fail Rev 16:13–21

4. Weisman HF, Bush DE, Mannisi JA, Bulkley BH (1985) Global

cardiac remodeling after acute myocardial infarction: a study in

the rat model. J Am Coll Cardiol 5:1355–1362

5. Anversa P, Olivetti G, Capasso JM (1991) Cellular basis of

ventricular remodeling after myocardial infarction. Am J Car-

diol 68:7D–16D

6. Bylund DB, Eikenberg DC, Hieble JP, Langer SZ, Lefkowitz

RJ, Minneman KP, Molinoff PB, Ruffolo RR Jr, Trendelenburg

U (1994) International union of pharmacology nomenclature of

adrenoceptors. Pharmacol Rev 46:121–136

7. Evans BA, Sato M, Sarwar M, Hutchinson DS, Summers RJ

(2010) Ligand-directed signalling at beta-adrenoceptors. Br J

Pharmacol 159:1022–1038

8. Alderman EL, Bourassa MG, Cohen LS, Davis KB, Kaiser GG,

Killip T, Mock MB, Pettinger M, Robertson TL (1990) Ten-year

follow-up of survival and myocardial infarction in the ran-

domized Coronary Artery Surgery Study. Circulation

82:1629–1646

9. Cleland JG, Freemantle N, Ball SG, Bonser RS, Camici P,

Chattopadhyay S, Dutka D, Eastaugh J, Hampton J, Large S,

Norell MS, Pennell DJ, Pepper J, Sanda S, Senior R, Smith D

(2003) The heart failure revascularisation trial (HEART):

rationale, design and methodology. Eur J Heart Fail 5:295–303

10. Asrih M, Mach F, Nencioni A, Dallegri F, Quercioli A,

Montecucco F (2013) Role of mitogen-activated protein kinase

pathways in multifactorial adverse cardiac remodeling associ-

ated with metabolic syndrome. Mediators Inflamm 2013:367245

11. Schaeffer HJ, Weber MJ (1999) Mitogen-activated protein

kinases: specific messages from ubiquitous messengers. Mol

Cell Biol 19:2435–2444

12. Muslin AJ (2008) MAPK signalling in cardiovascular health and

disease: molecular mechanisms and therapeutic targets. Clin Sci

115:203–218

13. Sabri A, Pak E, Alcott SA, Wilson BA, Steinberg SF (2000)

Coupling function of endogenous alpha(1)- and beta-adrenergic

receptors in mouse cardiomyocytes. Circ Res 86:1047–1053

Table 3 Affinity, selectivity of atenolol, metoprolol, bisoprolol and carvedilol [166]

Drug name LogKD values Selectivity ratios

b1 b2 b3 b1 versus b2 b1 versus b3

Atenolol -6.66 ± 0.05 -5.99 ± 0.14 -4.11 ± 0.07 4.7 354.8

Metoprolol -7.26 ± 0.07 -6.89 ± 0.09 -5.16 ± 0.12 2.3 125.9

Bisoprolol -7.83 ± 0.04 -6.70 ± 0.05 -5.67 ± 0.10 13.5 144.5

Carvedilol -8.75 ± 0.09 -9.40 ± 0.08 -8.30 ± 0.11 1/4.5 2.8

LogKD is used to evaluate the affinity of beta blocker to beta-ARs; the lower the value, the stronger the affinity

Heart Fail Rev

123

14. Zhang GX, Kimura S, Nishiyama A, Shokoji T, Rahman M, Yao

L, Nagai Y, Fujisawa Y, Miyatake A, Abe Y (2005) Cardiac

oxidative stress in acute and chronic isoproterenol-infused rats.

Cardiovasc Res 65:230–238

15. Peter PS, Brady JE, Yan L, Chen W, Engelhardt S, Wang Y,

Sadoshima J, Vatner SF, Vatner DE (2007) Inhibition of p38

alpha MAPK rescues cardiomyopathy induced by overexpressed

beta 2-adrenergic receptor, but not beta 1-adrenergic receptor.

J Clin Invest 117:1335–1343

16. Zheng M, Zhang SJ, Zhu WZ, Ziman B, Kobilka BK, Xiao RP

(2000) Beta 2-adrenergic receptor-induced p38 MAPK activation

is mediated by protein kinase A rather than by Gi or gbeta gamma

in adult mouse cardiomyocytes. J Biol Chem 275:40635–40640

17. Peterson KL (2002) Pressure overload hypertrophy and con-

gestive heart failure. Where is the ‘‘Achilles’ heel’’? J Am Coll

Cardiol 39:672–675

18. Rose BA, Force T, Wang Y (2010) Mitogen-activated protein

kinase signaling in the heart: angels versus demons in a heart-

breaking tale. Physiol Rev 90:1507–1546

19. Li T, Liu Z, Hu X, Ma K, Zhou C (2012) Involvement of ERK-

RSK cascade in phenylephrine-induced phosphorylation of

GATA4. Biochim Biophys Acta 1823:582–592

20. Busatto VC, Cunha V, Cicilini MA, Mill JG (1999) Differential

effects of isoproterenol on the activity of angiotensin-converting

enzyme in the rat heart and aorta. Braz J Med Biol Res 32:355–360

21. Noma T, Lemaire A, Naga Prasad SV, Barki-Harrington L,

Tilley DG, Chen J, Le Corvoisier P, Violin JD, Wei H, Lefko-

witz RJ, Rockman HA (2007) Beta-arrestin-mediated beta1-

adrenergic receptor transactivation of the EGFR confers car-

dioprotection. J Clin Invest 117:2445–2458

22. Wang Y, Su B, Sah VP, Brown JH, Han J, Chien KR (1998)

Cardiac hypertrophy induced by mitogen-activated protein

kinase kinase 7, a specific activator for c-Jun NH2-terminal

kinase in ventricular muscle cells. J Biol Chem 273:5423–5426

23. Bogoyevitch MA, Gillespie-Brown J, Ketterman AJ, Fuller SJ,

Ben-Levy R, Ashworth A, Marshall CJ, Sugden PH (1996)

Stimulation of the stress-activated mitogen-activated protein

kinase subfamilies in perfused heart. p38/RK mitogen-activated

protein kinases and c-Jun N-terminal kinases are activated by

ischemia/reperfusion. Circ Res 79:162–173

24. Liang Q, Molkentin JD (2003) Redefining the roles of p38 and JNK

signaling in cardiac hypertrophy: dichotomy between cultured

myocytes and animal models. J Mol Cell Cardiol 35:1385–1394

25. Petrich BG, Eloff BC, Lerner DL, Kovacs A, Saffitz JE, Ro-

senbaum DS, Wang Y (2004) Targeted activation of c-Jun

N-terminal kinase in vivo induces restrictive cardiomyopathy

and conduction defects. J Biol Chem 279:15330–15338

26. Choukroun G, Hajjar R, Kyriakis JM, Bonventre JV, Rosen-

zweig A, Force T (1998) Role of the stress-activated protein

kinases in endothelin-induced cardiomyocyte hypertrophy.

J Clin Invest 102:1311–1320

27. Liao P, Georgakopoulos D, Kovacs A, Zheng M, Lerner D, Pu H,

Saffitz J, Chien K, Xiao RP, Kass DA, Wang Y (2001) The in vivo

role of p38 MAP kinases in cardiac remodeling and restrictive

cardiomyopathy. Proc Natl Acad Sci USA 98:12283–12288

28. Bisognano JD, Weinberger HD, Bohlmeyer TJ, Pende A, Ray-

nolds MV, Sastravaha A, Roden R, Asano K, Blaxall BC, Wu SC,

Communal C, Singh K, Colucci W, Bristow MR, Port DJ (2000)

Myocardial-directed overexpression of the human beta(1)-

adrenergic receptor in transgenic mice. J Mol Cell Cardiol

32:817–830

29. Engelhardt S, Hein L, Wiesmann F, Lohse MJ (1999) Progres-

sive hypertrophy and heart failure in beta1-adrenergic receptor

transgenic mice. Proc Natl Acad Sci USA 96:7059–7064

30. Gaudin C, Ishikawa Y, Wight DC, Mahdavi V, Nadal-Ginard B,

Wagner TE, Vatner DE, Homcy CJ (1995) Overexpression of

Gs alpha protein in the hearts of transgenic mice. J Clin Invest

95:1676–1683

31. Antos CL, Frey N, Marx SO, Reiken S, Gaburjakova M, Rich-

ardson JA, Marks AR, Olson EN (2001) Dilated cardiomyopa-

thy and sudden death resulting from constitutive activation of

protein kinase a. Circ Res 89:997–1004

32. Lewin G, Matus M, Basu A, Frebel K, Rohsbach SP, Safronenko A,

Seidl MD, Stumpel F, Buchwalow I, Konig S, Engelhardt S, Lohse

MJ, Schmitz W, Muller FU (2009) Critical role of transcription

factor cyclic AMP response element modulator in beta1-adreno-

ceptor-mediated cardiac dysfunction. Circulation 119:79–88

33. Watson PA, Reusch JE, McCune SA, Leinwand LA, Luckey

SW, Konhilas JP, Brown DA, Chicco AJ, Sparagna GC, Long

CS, Moore RL (2007) Restoration of CREB function is linked to

completion and stabilization of adaptive cardiac hypertrophy in

response to exercise. Am J Physiol Heart Circ Physiol

293:H246–H259

34. Xiang Y, Kobilka BK (2003) Myocyte adrenoceptor signaling

pathways. Science 300:1530–1532

35. El-Armouche A, Eschenhagen T (2009) Beta-adrenergic stim-

ulation and myocardial function in the failing heart. Heart Fail

Rev 14:225–241

36. El-Armouche A, Rau T, Zolk O, Ditz D, Pamminger T, Zim-

mermann WH, Jackel E, Harding SE, Boknik P, Neumann J,

Eschenhagen T (2003) Evidence for protein phosphatase

inhibitor-1 playing an amplifier role in beta-adrenergic signaling

in cardiac myocytes. FASEB J 17:437–439

37. Carr AN, Schmidt AG, Suzuki Y, del Monte F, Sato Y, Lanner

C, Breeden K, Jing SL, Allen PB, Greengard P, Yatani A, Hoit

BD, Grupp IL, Hajjar RJ, DePaoli-Roach AA, Kranias EG

(2002) Type 1 phosphatase, a negative regulator of cardiac

function. Mol Cell Biol 22:4124–4135

38. Neumann J, Gupta RC, Schmitz W, Scholz H, Nairn AC, Wa-

tanabe AM (1991) Evidence for isoproterenol-induced phos-

phorylation of phosphatase inhibitor-1 in the intact heart. Circ

Res 69:1450–1457

39. Mulkey RM, Endo S, Shenolikar S, Malenka RC (1994)

Involvement of a calcineurin/inhibitor-1 phosphatase cascade in

hippocampal long-term depression. Nature 369:486–488

40. El-Armouche A, Bednorz A, Pamminger T, Ditz D, Didie M,

Dobrev D, Eschenhagen T (2006) Role of calcineurin and protein

phosphatase-2A in the regulation of phosphatase inhibitor-1 in

cardiac myocytes. Biochem Biophys Res Commun 346:700–706

41. Rehmann H, Schwede F, Doskeland SO, Wittinghofer A, Bos JL

(2003) Ligand-mediated activation of the cAMP-responsive guanine

nucleotide exchange factor Epac. J Biol Chem 278:38548–38556

42. Morel E, Marcantoni A, Gastineau M, Birkedal R, Rochais F,

Garnier A, Lompre AM, Vandecasteele G, Lezoualc’h F (2005)

cAMP-binding protein Epac induces cardiomyocyte hypertro-

phy. Circ Res 97:1296–1304

43. Lezoualc’h F, Metrich M, Hmitou I, Duquesnes N, Morel E

(2008) Small GTP-binding proteins and their regulators in car-

diac hypertrophy. J Mol Cell Cardiol 44:623–632

44. Bos JL (2006) Epac proteins: multi-purpose cAMP targets.

Trends Biochem Sci 31:680–686

45. Fu Y, Xiao H, Zhang Y (2012) Beta-adrenoceptor signaling

pathways mediate cardiac pathological remodeling. Front Biosci

4:1625–1637

46. Berthouze-Duquesnes M, Lucas A, Sauliere A, Sin YY, Laurent

AC, Gales C, Baillie G, Lezoualc’h F (2013) Specific interac-tions between Epac1, beta-arrestin2 and PDE4D5 regulate beta-

adrenergic receptor subtype differential effects on cardiac

hypertrophic signaling. Cell Signal 25:970–980

47. Metrich M, Lucas A, Gastineau M, Samuel JL, Heymes C, Morel

E, Lezoualc’h F (2008) Epac mediates beta-adrenergic receptor-

induced cardiomyocyte hypertrophy. Circ Res 102:959–965

Heart Fail Rev

123

48. Metrich M, Laurent AC, Breckler M, Duquesnes N, Hmitou I,

Courillau D, Blondeau JP, Crozatier B, Lezoualc’h F, Morel E

(2010) Epac activation induces histone deacetylase nuclear

export via a Ras-dependent signalling pathway. Cell Signal

22:1459–1468

49. Chiang CS, Huang CH, Chieng H, Chang YT, Chang D, Chen

JJ, Chen YC, Chen YH, Shin HS, Campbell KP, Chen CC

(2009) The Ca(v)3.2 T-type Ca(2 ?) channel is required for

pressure overload-induced cardiac hypertrophy in mice. Circ

Res 104:522–530

50. Onohara N, Nishida M, Inoue R, Kobayashi H, Sumimoto H,

Sato Y, Mori Y, Nagao T, Kurose H (2006) TRPC3 and TRPC6

are essential for angiotensin II-induced cardiac hypertrophy.

EMBO J 25:5305–5316

51. Kuwahara K, Wang Y, McAnally J, Richardson JA, Bassel-

Duby R, Hill JA, Olson EN (2006) TRPC6 fulfills a calcineurin

signaling circuit during pathologic cardiac remodeling. J Clin

Invest 116:3114–3126

52. Tandan S, Wang Y, Wang TT, Jiang N, Hall DD, Hell JW, Luo X,

Rothermel BA, Hill JA (2009) Physical and functional interaction

between calcineurin and the cardiac L-type Ca2 ? channel. Circ

Res 105:51–60

53. Semsarian C, Ahmad I, Giewat M, Georgakopoulos D, Schmitt

JP, McConnell BK, Reiken S, Mende U, Marks AR, Kass DA,

Seidman CE, Seidman JG (2002) The L-type calcium channel

inhibitor diltiazem prevents cardiomyopathy in a mouse model.

J Clin Invest 109:1013–1020

54. Liao Y, Asakura M, Takashima S, Ogai A, Asano Y, Asanuma

H, Minamino T, Tomoike H, Hori M, Kitakaze M (2005)

Benidipine, a long-acting calcium channel blocker, inhibits

cardiac remodeling in pressure-overloaded mice. Cardiovasc

Res 65:879–888

55. Chen X, Nakayama H, Zhang X, Ai X, Harris DM, Tang M,

Zhang H, Szeto C, Stockbower K, Berretta RM, Eckhart AD,

Koch WJ, Molkentin JD, Houser SR (2011) Calcium influx

through Cav1.2 is a proximal signal for pathological cardio-

myocyte hypertrophy. J Mol Cell Cardiol 50:460–470

56. Gao H, Wang F, Wang W, Makarewich CA, Zhang H, Kubo H,

Berretta RM, Barr LA, Molkentin JD, Houser SR (2012)

Ca(2 ?) influx through L-type Ca(2 ?) channels and transient

receptor potential channels activates pathological hypertrophy

signaling. J Mol Cell Cardiol 53:657–667

57. Molkentin JD, Lu JR, Antos CL, Markham B, Richardson J,

Robbins J, Grant SR, Olson EN (1998) A calcineurin-dependent

transcriptional pathway for cardiac hypertrophy. Cell

93:215–228

58. Zhang CL, McKinsey TA, Chang S, Antos CL, Hill JA, Olson

EN (2002) Class II histone deacetylases act as signal-responsive

repressors of cardiac hypertrophy. Cell 110:479–488

59. Backs J, Backs T, Neef S, Kreusser MM, Lehmann LH, Patrick

DM, Grueter CE, Qi X, Richardson JA, Hill JA, Katus HA,

Bassel-Duby R, Maier LS, Olson EN (2009) The delta isoform

of CaM kinase II is required for pathological cardiac hypertro-

phy and remodeling after pressure overload. Proc Natl Acad Sci

USA 106:2342–2347

60. Wright SC, Schellenberger U, Ji L, Wang H, Larrick JW (1997)

Calmodulin-dependent protein kinase II mediates signal trans-

duction in apoptosis. FASEB J 11:843–849

61. Ishitani T, Kishida S, Hyodo-Miura J, Ueno N, Yasuda J,

Waterman M, Shibuya H, Moon RT, Ninomiya-Tsuji J, Mat-

sumoto K (2003) The TAK1-NLK mitogen-activated protein

kinase cascade functions in the Wnt-5a/Ca(2 ?) pathway to

antagonize Wnt/beta-catenin signaling. Mol Cell Biol

23:131–139

62. Takeda K, Matsuzawa A, Nishitoh H, Tobiume K, Kishida S,

Ninomiya-Tsuji J, Matsumoto K, Ichijo H (2004) Involvement

of ASK1 in Ca2 ? -induced p38 MAP kinase activation. EMBO

Rep 5:161–166

63. Chang HY, Nishitoh H, Yang X, Ichijo H, Baltimore D (1998)

Activation of apoptosis signal-regulating kinase 1 (ASK1) by

the adapter protein Daxx. Science 281:1860–1863

64. Zhu WZ, Wang SQ, Chakir K, Yang D, Zhang T, Brown JH,

Devic E, Kobilka BK, Cheng H, Xiao RP (2003) Linkage of

beta1-adrenergic stimulation to apoptotic heart cell death

through protein kinase A-independent activation of Ca2 ?/cal-

modulin kinase II. J Clin Invest 111:617–625

65. Zhu W, Woo AY, Yang D, Cheng H, Crow MT, Xiao RP (2007)

Activation of CaMKIIdeltaC is a common intermediate of

diverse death stimuli-induced heart muscle cell apoptosis. J Biol

Chem 282:10833–10839

66. Cantley LC (2002) The phosphoinositide 3-kinase pathway.

Science 296:1655–1657

67. Morisco C, Zebrowski D, Condorelli G, Tsichlis P, Vatner SF,

Sadoshima J (2000) The Akt-glycogen synthase kinase 3beta

pathway regulates transcription of atrial natriuretic factor induced

by beta-adrenergic receptor stimulation in cardiac myocytes.

J Biol Chem 275:14466–14475

68. Schluter KD, Goldberg Y, Taimor G, Schafer M, Piper HM

(1998) Role of phosphatidylinositol 3-kinase activation in the

hypertrophic growth of adult ventricular cardiomyocytes. Car-

diovasc Res 40:174–181

69. Jo SH, Leblais V, Wang PH, Crow MT, Xiao RP (2002)

Phosphatidylinositol 3-kinase functionally compartmentalizes

the concurrent G(s) signaling during beta2-adrenergic stimula-

tion. Circ Res 91:46–53

70. Leblais V, Jo SH, Chakir K, Maltsev V, Zheng M, Crow MT, Wang

W, Lakatta EG, Xiao RP (2004) Phosphatidylinositol 3-kinase

offsets cAMP-mediated positive inotropic effect via inhibiting

Ca2 ? influx in cardiomyocytes. Circ Res 95:1183–1190

71. Zhu X, Wang L, Liu R, Flutter B, Li S, Ding J, Tao H, Liu C,Sun M, Gao B (2010) COMBODY: one-domain antibody mul-

timer with improved avidity. Immunol Cell Biol 88:667–675

72. Crackower MA, Oudit GY, Kozieradzki I, Sarao R, Sun H,

Sasaki T, Hirsch E, Suzuki A, Shioi T, Irie-Sasaki J, Sah R,

Cheng HY, Rybin VO, Lembo G, Fratta L, Oliveira-dos-Santos

AJ, Benovic JL, Kahn CR, Izumo S, Steinberg SF, Wymann

MP, Backx PH, Penninger JM (2002) Regulation of myocardial

contractility and cell size by distinct PI3K-PTEN signaling

pathways. Cell 110:737–749

73. McMullen JR, Shioi T, Zhang L, Tarnavski O, Sherwood MC,

Kang PM, Izumo S (2003) Phosphoinositide 3-kinase(p110al-

pha) plays a critical role for the induction of physiological, but

not pathological, cardiac hypertrophy. Proc Natl Acad Sci USA

100:12355–12360

74. Patrucco E, Notte A, Barberis L, Selvetella G, Maffei A,

Brancaccio M, Marengo S, Russo G, Azzolino O, Rybalkin SD,

Silengo L, Altruda F, Wetzker R, Wymann MP, Lembo G,

Hirsch E (2004) PI3Kgamma modulates the cardiac response to

chronic pressure overload by distinct kinase-dependent and -

independent effects. Cell 118:375–387

75. Naga Prasad SV, Esposito G, Mao L, Koch WJ, Rockman HA

(2000) Gbetagamma-dependent phosphoinositide 3-kinase acti-

vation in hearts with in vivo pressure overload hypertrophy.

J Biol Chem 275:4693–4698

76. Oudit GY, Crackower MA, Eriksson U, Sarao R, Kozieradzki I,

Sasaki T, Irie-Sasaki J, Gidrewicz D, Rybin VO, Wada T,

Steinberg SF, Backx PH, Penninger JM (2003) Phosphoinositide

3-kinase gamma-deficient mice are protected from isoprotere-

nol-induced heart failure. Circulation 108:2147–2152

77. Guo D, Kassiri Z, Basu R, Chow FL, Kandalam V, Damilano F,

Liang W, Izumo S, Hirsch E, Penninger JM, Backx PH, Oudit

GY (2010) Loss of PI3Kgamma enhances cAMP-dependent

Heart Fail Rev

123

MMP remodeling of the myocardial N-cadherin adhesion

complexes and extracellular matrix in response to early bio-

mechanical stress. Circ Res 107:1275–1289

78. Sands WA, Palmer TM (2008) Regulating gene transcription in

response to cyclic AMP elevation. Cell Signal 20:460–466

79. Henderson BC, Sen U, Reynolds C, Moshal KS, Ovechkin A,

Tyagi N, Kartha GK, Rodriguez WE, Tyagi SC (2007) Reversal

of systemic hypertension-associated cardiac remodeling in

chronic pressure overload myocardium by ciglitazone. Int J Biol

Sci 3:385–392

80. Rizzi E, Castro MM, Prado CM, Silva CA, Fazan R Jr, Rossi

MA, Tanus-Santos JE, Gerlach RF (2010) Matrix metallopro-

teinase inhibition improves cardiac dysfunction and remodeling

in 2-kidney, 1-clip hypertension. J Card Fail 16:599–608

81. Matsusaka H, Ide T, Matsushima S, Ikeuchi M, Kubota T,

Sunagawa K, Kinugawa S, Tsutsui H (2006) Targeted deletion

of matrix metalloproteinase 2 ameliorates myocardial remodel-

ing in mice with chronic pressure overload. Hypertension

47:711–717

82. Lacchini R, Jacob-Ferreira AL, Luizon MR, Gasparini S,

Ferreira-Sae MC, Schreiber R, Nadruz W Jr, Tanus-Santos JE

(2012) Common matrix metalloproteinase 2 gene haplotypes

may modulate left ventricular remodelling in hypertensive

patients. J Hum Hypertens 26:171–177

83. Chesley A, Lundberg MS, Asai T, Xiao RP, Ohtani S, Lakatta

EG, Crow MT (2000) The beta(2)-adrenergic receptor delivers

an antiapoptotic signal to cardiac myocytes through G(i)-

dependent coupling to phosphatidylinositol 30-kinase. Circ Res

87:1172–1179

84. Zhu W, Zeng X, Zheng M, Xiao RP (2005) The enigma of

beta2-adrenergic receptor Gi signaling in the heart: the good, the

bad, and the ugly. Circ Res 97:507–509

85. Yano N, Ianus V, Zhao TC, Tseng A, Padbury JF, Tseng YT

(2007) A novel signaling pathway for beta-adrenergic receptor-

mediated activation of phosphoinositide 3-kinase in H9c2

cardiomyocytes. Am J Physiol Heart Circ Physiol 293:H385–

H393

86. Zhang W, Yano N, Deng M, Mao Q, Shaw SK, Tseng YT

(2011) Beta-Adrenergic receptor-PI3K signaling crosstalk in

mouse heart: elucidation of immediate downstream signaling

cascades. PLoS ONE 6:e26581

87. Ning Q, Jian XD, Liu J, Lin DW, Liu F, Zhang ZC, Zhao B

(2010) Experimental therapy of penehyclidine hydrochloride on

paraquat-induced acute lung injury. Zhonghua Lao Dong Wei

Sheng Zhi Ye Bing Za Zhi 28:667–670

88. Dupont Jensen J, Laenkholm AV, Knoop A, Ewertz M, Bandaru

R, Liu W, Hackl W, Barrett JC, Gardner H (2011) PIK3CA

mutations may be discordant between primary and correspond-

ing metastatic disease in breast cancer. Clin Cancer Res

17:667–677

89. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y,

Greenberg ME (1997) Akt phosphorylation of BAD couples

survival signals to the cell-intrinsic death machinery. Cell

91:231–241

90. del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G

(1997) Interleukin-3-induced phosphorylation of BAD through

the protein kinase Akt. Science 278:687–689

91. Brunet A, Datta SR, Greenberg ME (2001) Transcription-

dependent and -independent control of neuronal survival by the

PI3K–Akt signaling pathway. Curr Opin Neurobiol 11:297–305

92. Sugimoto M, Nakayama M, Goto TM, Amano M, Komori K,

Kaibuchi K (2007) Rho-kinase phosphorylates eNOS at threo-

nine 495 in endothelial cells. Biochem Biophys Res Commun

361:462–467

93. Woodgett JR (1990) Molecular cloning and expression of gly-

cogen synthase kinase-3/factor A. EMBO J 9:2431–2438

94. Morisco C, Seta K, Hardt SE, Lee Y, Vatner SF, Sadoshima J

(2001) Glycogen synthase kinase 3beta regulates GATA4 in

cardiac myocytes. J Biol Chem 276:28586–28597

95. Haq S, Choukroun G, Kang ZB, Ranu H, Matsui T, Rosenzweig

A, Molkentin JD, Alessandrini A, Woodgett J, Hajjar R,

Michael A, Force T (2000) Glycogen synthase kinase-3beta is a

negative regulator of cardiomyocyte hypertrophy. J Cell Biol

151:117–130

96. Webb IG, Nishino Y, Clark JE, Murdoch C, Walker SJ, Ma-

kowski MR, Botnar RM, Redwood SR, Shah AM, Marber MS

(2010) Constitutive glycogen synthase kinase-3alpha/beta

activity protects against chronic beta-adrenergic remodelling of

the heart. Cardiovasc Res 87:494–503

97. Lal H, Zhou J, Ahmad F, Zaka R, Vagnozzi RJ, Decaul M,

Woodgett J, Gao E, Force T (2012) Glycogen synthase kinase-

3alpha limits ischemic injury, cardiac rupture, post-myocardial

infarction remodeling and death. Circulation 125:65–75

98. Zhou J, Lal H, Chen X, Shang X, Song J, Li Y, Kerkela R,

Doble BW, MacAulay K, DeCaul M, Koch WJ, Farber J,

Woodgett J, Gao E, Force T (2010) GSK-3alpha directly regu-

lates beta-adrenergic signaling and the response of the heart to

hemodynamic stress in mice. J Clin Invest 120:2280–2291

99. Zhai P, Gao S, Holle E, Yu X, Yatani A, Wagner T, Sadoshima J

(2007) Glycogen synthase kinase-3alpha reduces cardiac growth

and pressure overload-induced cardiac hypertrophy by inhibition

of extracellular signal-regulated kinases. J Biol Chem

282:33181–33191

100. Huang J, Manning BD (2008) The TSC1–TSC2 complex: a

molecular switchboard controlling cell growth. Biochem J

412:179–190

101. Matsuda T, Zhai P, Maejima Y, Hong C, Gao S, Tian B, Goto K,

Takagi H, Tamamori-Adachi M, Kitajima S, Sadoshima J

(2008) Distinct roles of GSK-3alpha and GSK-3beta phos-

phorylation in the heart under pressure overload. Proc Natl Acad

Sci USA 105:20900–20905

102. Skurk C, Izumiya Y, Maatz H, Razeghi P, Shiojima I, Sandri M,

Sato K, Zeng L, Schiekofer S, Pimentel D, Lecker S, Taegt-

meyer H, Goldberg AL, Walsh K (2005) The FOXO3a tran-

scription factor regulates cardiac myocyte size downstream of

AKT signaling. J Biol Chem 280:20814–20823

103. Ni YG, Berenji K, Wang N, Oh M, Sachan N, Dey A, Cheng J,

Lu G, Morris DJ, Castrillon DH, Gerard RD, Rothermel BA,

Hill JA (2006) Foxo transcription factors blunt cardiac hyper-

trophy by inhibiting calcineurin signaling. Circulation

114:1159–1168

104. Fang CX, Dong F, Thomas DP, Ma H, He L, Ren J (2008)

Hypertrophic cardiomyopathy in high-fat diet-induced obesity:

role of suppression of forkhead transcription factor and atrophy

gene transcription. Am J Physiol Heart Circ Physiol 295:H1206–

H1215

105. Tremblay ML, Giguere V (2008) Phosphatases at the heart of

FoxO metabolic control. Cell Metab 7:101–103

106. Ferdous A, Battiprolu PK, Ni YG, Rothermel BA, Hill JA

(2010) FoxO, autophagy, and cardiac remodeling. J Cardiovasc

Transl Res 3:355–364

107. Emorine LJ, Marullo S, Briend-Sutren MM, Patey G, Tate K,

Delavier-Klutchko C, Strosberg AD (1989) Molecular charac-

terization of the human beta 3-adrenergic receptor. Science

245:1118–1121

108. Simard PM, Atgie C, Mauriege P, D’Allaire F, Bukowiecki LJ

(1994) Comparison of the lipolytic effects of norepinephrine and

BRL 37344 in rat brown and white adipocytes. Obes Res

2:424–431

109. Hutchinson DS, Chernogubova E, Dallner OS, Cannon B,

Bengtsson T (2005) Beta-adrenoceptors, but not alpha-adreno-

ceptors, stimulate AMP-activated protein kinase in brown

Heart Fail Rev

123

adipocytes independently of uncoupling protein-1. Diabetologia

48:2386–2395

110. Cheng HJ, Zhang ZS, Onishi K, Ukai T, Sane DC, Cheng CP

(2001) Upregulation of functional beta(3)-adrenergic receptor in

the failing canine myocardium. Circ Res 89:599–606

111. Zhao Q, Wu TG, Jiang ZF, Chen GW, Lin Y, Wang LX (2007)

Effect of beta-blockers on beta3-adrenoceptor expression in

chronic heart failure. Cardiovasc Drugs Ther 21:85–90

112. Moens AL, Leyton-Mange JS, Niu X, Yang R, Cingolani O,

Arkenbout EK, Champion HC, Bedja D, Gabrielson KL, Chen J,

Xia Y, Hale AB, Channon KM, Halushka MK, Barker N, Wuyts

FL, Kaminski PM, Wolin MS, Kass DA, Barouch LA (2009)

Adverse ventricular remodeling and exacerbated NOS uncou-

pling from pressure-overload in mice lacking the beta3-adre-

noreceptor. J Mol Cell Cardiol 47:576–585

113. Niu X, Watts VL, Cingolani OH, Sivakumaran V, Leyton-Mange

JS, Ellis CL, Miller KL, Vandegaer K, Bedja D, Gabrielson KL,

Paolocci N, Kass DA, Barouch LA (2012) Cardioprotective effect

of beta-3 adrenergic receptor agonism: role of neuronal nitric

oxide synthase. J Am Coll Cardiol 59:1979–1987

114. Gauthier C, Tavernier G, Charpentier F, Langin D, Le Marec H

(1996) Functional beta3-adrenoceptor in the human heart. J Clin

Invest 98:556–562

115. Gauthier C, Leblais V, Kobzik L, Trochu JN, Khandoudi N, Bril

A, Balligand JL, Le Marec H (1998) The negative inotropic

effect of beta3-adrenoceptor stimulation is mediated by activa-

tion of a nitric oxide synthase pathway in human ventricle.

J Clin Invest 102:1377–1384

116. Varghese P, Harrison RW, Lofthouse RA, Georgakopoulos D,

Berkowitz DE, Hare JM (2000) Beta(3)-adrenoceptor deficiency

blocks nitric oxide-dependent inhibition of myocardial con-

tractility. J Clin Invest 106:697–703

117. Ignarro LJ (1999) Nitric oxide: a unique endogenous signaling

molecule in vascular biology. Biosci Rep 19:51–71

118. Francis SH, Busch JL, Corbin JD, Sibley D (2010) cGMP-

dependent protein kinases and cGMP phosphodiesterases in

nitric oxide and cGMP action. Pharmacol Rev 62:525–563

119. Hofmann F (2005) The biology of cyclic GMP-dependent pro-

tein kinases. J Biol Chem 280:1–4

120. Hofmann F, Bernhard D, Lukowski R, Weinmeister P (2009)

cGMP regulated protein kinases (cGK). Handb Exp Pharmacol

191:137–162

121. Wegener JW, Nawrath H, Wolfsgruber W, Kuhbandner S,

Werner C, Hofmann F, Feil R (2002) cGMP-dependent protein

kinase I mediates the negative inotropic effect of cGMP in the

murine myocardium. Circ Res 90:18–20

122. Godecke A, Heinicke T, Kamkin A, Kiseleva I, Strasser RH,

Decking UK, Stumpe T, Isenberg G, Schrader J (2001) Inotropic

response to beta-adrenergic receptor stimulation and anti-

adrenergic effect of ACh in endothelial NO synthase-deficient

mouse hearts. J Physiol 532:195–204

123. Schroder F, Klein G, Fiedler B, Bastein M, Schnasse N, Hillmer

A, Ames S, Gambaryan S, Drexler H, Walter U, Lohmann SM,

Wollert KC (2003) Single L-type Ca(2 ?) channel regulation by

cGMP-dependent protein kinase type I in adult cardiomyocytes

from PKG I transgenic mice. Cardiovasc Res 60:268–277

124. Brixius K, Bloch W, Pott C, Napp A, Krahwinkel A, Ziskoven

C, Koriller M, Mehlhorn U, Hescheler J, Fleischmann B,

Schwinger RH (2004) Mechanisms of beta 3-adrenoceptor-

induced eNOS activation in right atrial and left ventricular

human myocardium. Br J Pharmacol 143:1014–1022

125. Brixius K, Bloch W, Ziskoven C, Bolck B, Napp A, Pott C,

Steinritz D, Jiminez M, Addicks K, Giacobino JP, Schwinger

RH (2006) Beta3-adrenergic eNOS stimulation in left ventric-

ular murine myocardium. Can J Physiol Pharmacol 84:1051–

1060

126. Napp A, Brixius K, Pott C, Ziskoven C, Boelck B, Mehlhorn U,

Schwinger RH, Bloch W (2009) Effects of the beta3-adrenergic

agonist BRL 37344 on endothelial nitric oxide synthase phos-

phorylation and force of contraction in human failing myocar-

dium. J Card Fail 15:57–67

127. Bauer PM, Fulton D, Boo YC, Sorescu GP, Kemp BE, Jo H,

Sessa WC (2003) Compensatory phosphorylation and protein-

protein interactions revealed by loss of function and gain of

function mutants of multiple serine phosphorylation sites in

endothelial nitric-oxide synthase. J Biol Chem 278:14841–

14849

128. Fleming I, Busse R (2003) Molecular mechanisms involved in

the regulation of the endothelial nitric oxide synthase. Am J

Physiol Regul Integr Comp Physiol 284:R1–R12

129. Kolluru GK, Siamwala JH, Chatterjee S (2010) eNOS phos-

phorylation in health and disease. Biochimie 92:1186–1198

130. Yin F, Wang YY, Du JH, Li C, Lu ZZ, Han C, Zhang YY (2006)

Noncanonical cAMP pathway and p38 MAPK mediate beta2-

adrenergic receptor-induced IL-6 production in neonatal mouse

cardiac fibroblasts. J Mol Cell Cardiol 40:384–393

131. Seeland U, Schaffer A, Selejan S, Hohl M, Reil JC, Muller P,

Rosenkranz S, Bohm M (2009) Effects of AT1- and beta-

adrenergic receptor antagonists on TGF-beta1-induced fibrosis

in transgenic mice. Eur J Clin Invest 39:851–859

132. Dostal DE (2000) The cardiac renin-angiotensin system: novel

signaling mechanisms related to cardiac growth and function.

Regul Pept 91:1–11

133. Leenen FH, White R, Yuan B (2001) Isoproterenol-induced cardiac

hypertrophy: role of circulatory versus cardiac renin-angiotensin

system. Am J Physiol Heart Circ Physiol 281:H2410–H2416

134. Matsui Y, Jia N, Okamoto H, Kon S, Onozuka H, Akino M, Liu

L, Morimoto J, Rittling SR, Denhardt D, Kitabatake A, Uede T

(2004) Role of osteopontin in cardiac fibrosis and remodeling in

angiotensin II-induced cardiac hypertrophy. Hypertension

43:1195–1201

135. Haghikia A, Stapel B, Hoch M, Hilfiker-Kleiner D (2011)

STAT3 and cardiac remodeling. Heart Fail Rev 16:35–47

136. Dobaczewski M, Chen W, Frangogiannis NG (2011) Trans-

forming growth factor (TGF)-beta signaling in cardiac remod-

eling. J Mol Cell Cardiol 51:600–606

137. Hsu SD, Lin FM, Wu WY, Liang C, Huang WC, Chan WL, Tsai

WT, Chen GZ, Lee CJ, Chiu CM, Chien CH, Wu MC, Huang

CY, Tsou AP, Huang HD (2011) miRTarBase: a database

curates experimentally validated microRNA-target interactions.

Nucleic Acids Res 39:D163–D169

138. Essaghir A, Toffalini F, Knoops L, Kallin A, van Helden J,

Demoulin JB (2010) Transcription factor regulation can be

accurately predicted from the presence of target gene signatures

in microarray gene expression data. Nucleic Acids Res 38:e120

139. Keshava Prasad TS, Goel R, Kandasamy K, Keerthikumar S,

Kumar S, Mathivanan S, Telikicherla D, Raju R, Shafreen B,

Venugopal A, Balakrishnan L, Marimuthu A, Banerjee S, So-

manathan DS, Sebastian A, Rani S, Ray S, Harrys Kishore CJ,

Kanth S, Ahmed M, Kashyap MK, Mohmood R, Ramachandra

YL, Krishna V, Rahiman BA, Mohan S, Ranganathan P, Ram-

abadran S, Chaerkady R, Pandey A (2009) Human protein ref-

erence database-2009 update. Nucleic Acids Res 37:D767–D772

140. Sun W, Julie Li YS, Huang HD, Shyy JY, Chien S (2010)

microRNA: a master regulator of cellular processes for bioen-

gineering systems. Annu Rev Biomed Eng 12:1–27

141. Liu LZ, Li C, Chen Q, Jing Y, Carpenter R, Jiang Y, Kung HF,

Lai L, Jiang BH (2011) MiR-21 induced angiogenesis through

AKT and ERK activation and HIF-1alpha expression. PLoS

ONE 6:e19139

142. Lal A, Thomas MP, Altschuler G, Navarro F, O’Day E, Li XL,

Concepcion C, Han YC, Thiery J, Rajani DK, Deutsch A,

Heart Fail Rev

123

Hofmann O, Ventura A, Hide W, Lieberman J (2011) Capture of

microRNA-bound mRNAs identifies the tumor suppressor miR-

34a as a regulator of growth factor signaling. PLoS Genet

7:e1002363

143. Frigerio M, Roubina E (2005) Drugs for left ventricular

remodeling in heart failure. Am J Cardiol 96:10L–18L

144. Foody JM, Farrell MH, Krumholz HM (2002) Beta-Blocker

therapy in heart failure: scientific review. JAMA 287:883–889

145. CIBIS-II Investigators and Committees (1999) The cardiac

insufficiency bisoprolol study II (CIBIS-II): a randomised trial.

Lancet 353:9–13

146. Lechat P, Escolano S, Golmard JL, Lardoux H, Witchitz S,

Henneman JA, Maisch B, Hetzel M, Jaillon P, Boissel JP, Mallet

A (1997) Prognostic value of bisoprolol-induced hemodynamic

effects in heart failure during the Cardiac Insufficiency BIso-

prolol Study (CIBIS). Circulation 96:2197–2205

147. Yoshitomi Y, Kojima S, Yano M, Sugi T, Matsumoto Y, Ku-

ramochi M (2000) Long-term effects of bisoprolol compared

with imidapril on left ventricular remodeling after reperfusion in

acute myocardial infarction: an angiographic study in patients

with maintained vessel patency. Am Heart J 140:E27

148. Waagstein F, Bristow MR, Swedberg K, Camerini F, Fowler

MB, Silver MA, Gilbert EM, Johnson MR, Goss FG, Hjalmar-

son A (1993) Beneficial effects of metoprolol in idiopathic

dilated cardiomyopathy. Metoprolol in Dilated Cardiomyopathy

(MDC) Trial Study Group. Lancet 342:1441–1446

149. MERIT-HF Study Group (1999) Effect of metoprolol CR/XL in

chronic heart failure: metoprolol CR/XL randomised interven-

tion trial in congestive heart failure (MERIT-HF). Lancet

353:2001–2007

150. Ahmed MI, Aban I, Lloyd SG, Gupta H, Howard G, Inusah S,

Peri K, Robinson J, Smith P, McGiffin DC, Schiros CG, Denney

T Jr, Dell’Italia LJ (2012) A randomized controlled phase IIb

trial of beta(1)-receptor blockade for chronic degenerative mitral

regurgitation. J Am Coll Cardiol 60:833–838

151. Colucci WS, Packer M, Bristow MR, Gilbert EM, Cohn JN,

Fowler MB, Krueger SK, Hershberger R, Uretsky BF, Bowers

JA, Sackner-Bernstein JD, Young ST, Holcslaw TL, Lukas MA

(1996) Carvedilol inhibits clinical progression in patients with

mild symptoms of heart failure. US Carvedilol Heart Failure

Study Group. Circulation 94:2800–2806

152. Australia/New Zealand Heart Failure Research Collaborative

Group (1997) Randomised, placebo-controlled trial of carvedi-

lol in patients with congestive heart failure due to ischaemic

heart disease. Australia/New Zealand Heart Failure. Lancet

349:375–380

153. Basu S, Senior R, Raval U, van der Does R, Bruckner T, Lahiri

A (1997) Beneficial effects of intravenous and oral carvedilol

treatment in acute myocardial infarction. A placebo-controlled,

randomized trial. Circulation 96:183–191

154. Leonetti Luparini R, Celli V, Piccirillo G, Guidi V, Cacciafesta

M, Marigliano V (1999) Carvedilol in elderly patients with

chronic heart failure, a 12 weeks randomized, placebo con-

trolled open trial. Arch Gerontol Geriatr 29:275–282

155. Lowes BD, Gill EA, Abraham WT, Larrain JR, Robertson AD,

Bristow MR, Gilbert EM (1999) Effects of carvedilol on left

ventricular mass, chamber geometry, and mitral regurgitation in

chronic heart failure. Am J Cardiol 83:1201–1205

156. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F,

Smith R, Dunkman WB, Loeb H, Wong M et al (1991) A

comparison of enalapril with hydralazine-isosorbide dinitrate in

the treatment of chronic congestive heart failure. N Engl J Med

325:303–310

157. Doi M, Yano M, Kobayashi S, Kohno M, Tokuhisa T, Okuda S,

Suetsugu M, Hisamatsu Y, Ohkusa T, Kohno M, Matsuzaki M

(2002) Propranolol prevents the development of heart failure by

restoring FKBP12.6-mediated stabilization of ryanodine recep-

tor. Circulation 105:1374–1379

158. Reiken S, Wehrens XH, Vest JA, Barbone A, Klotz S, Mancini

D, Burkhoff D, Marks AR (2003) Beta-blockers restore calcium

release channel function and improve cardiac muscle perfor-

mance in human heart failure. Circulation 107:2459–2466

159. Sun YL, Hu SJ, Wang LH, Hu Y, Zhou JY (2005) Effect of beta-

blockers on cardiac function and calcium handling protein in

postinfarction heart failure rats. Chest 128:1812–1821

160. Bartholomeu JB, Vanzelli AS, Rolim NP, Ferreira JC, Bechara

LR, Tanaka LY, Rosa KT, Alves MM, Medeiros A, Mattos KC,

Coelho MA, Irigoyen MC, Krieger EM, Krieger JE, Negrao CE,

Ramires PR, Guatimosim S, Brum PC (2008) Intracellular

mechanisms of specific beta-adrenoceptor antagonists involved

in improved cardiac function and survival in a genetic model of

heart failure. J Mol Cell Cardiol 45:240–249

161. Prabhu SD, Wang G, Luo J, Gu Y, Ping P, Chandrasekar B

(2003) Beta-adrenergic receptor blockade modulates Bcl-

X(S) expression and reduces apoptosis in failing myocardium.

J Mol Cell Cardiol 35:483–493

162. Zhou X, Ma L, Habibi J, Whaley-Connell A, Hayden MR,

Tilmon RD, Brown AN, Kim JA, Demarco VG, Sowers JR

(2010) Nebivolol improves diastolic dysfunction and myocardial

remodeling through reductions in oxidative stress in the Zucker

obese rat. Hypertension 55:880–888

163. Cimmino G, Ibanez B, Giannarelli C, Prat-Gonzalez S, Hutter R,

Garcia M, Sanz J, Fuster V, Badimon JJ (2011) Carvedilol

administration in acute myocardial infarction results in stronger

inhibition of early markers of left ventricular remodeling than

metoprolol. Int J Cardiol 153:256–261

164. Zaca V, Rastogi S, Mishra S, Wang M, Sharov VG, Gupta RC,

Goldstein S, Sabbah HN (2009) Atenolol is inferior to meto-

prolol in improving left ventricular function and preventing

ventricular remodeling in dogs with heart failure. Cardiology

112:294–302

165. Bristow MR, Ginsburg R, Umans V, Fowler M, Minobe W,

Rasmussen R, Zera P, Menlove R, Shah P, Jamieson S et al

(1986) Beta 1- and beta 2-adrenergic-receptor subpopulations in

nonfailing and failing human ventricular myocardium: coupling

of both receptor subtypes to muscle contraction and selective

beta 1-receptor down-regulation in heart failure. Circ Res

59:297–309

166. Baker JG (2005) The selectivity of beta-adrenoceptor antago-

nists at the human beta1, beta2 and beta3 adrenoceptors. Br J

Pharmacol 144:317–322

167. Hou Y, Sun Y, Shan H, Li X, Zhang M, Zhou X, Xing S, Sun H,

Chu W, Qiao G, Lu Y (2012) Beta-adrenoceptor regulates

miRNA expression in rat heart. Med Sci Monit 18:BR309–

BR314

168. Zhu W, Yang L, Shan H, Zhang Y, Zhou R, Su Z, Du Z (2011)

MicroRNA expression analysis: clinical advantage of propran-

olol reveals key microRNAs in myocardial infarction. PLoS

ONE 6:e14736

169. Lu Y, Zhang Y, Shan H, Pan Z, Li X, Li B, Xu C, Zhang B,

Zhang F, Dong D, Song W, Qiao G, Yang B (2009) MicroRNA-

1 downregulation by propranolol in a rat model of myocardial

infarction: a new mechanism for ischaemic cardioprotection.

Cardiovasc Res 84:434–441

170. Ye H, Ling S, Castillo AC, Thomas B, Long B, Qian J, Perez-

Polo JR, Ye Y, Chen X, Birnbaum Y (2013) Nebivolol induces

distinct changes in profibrosis microRNA expression compared

with atenolol, in salt-sensitive hypertensive rats. Hypertension

61:1008–1013

171. Tran Quang T, Rozec B, Audigane L, Gauthier C (2009)

Investigation of the different adrenoceptor targets of nebivolol

enantiomers in rat thoracic aorta. Br J Pharmacol 156:601–608

Heart Fail Rev

123

172. CIBIS Investigators and Committees (1994) A randomized trial

of beta-blockade in heart failure. The Cardiac Insufficiency

Bisoprolol Study (CIBIS). CIBIS Investigators and Committees.

Circulation 90:1765–1773

173. Beta-Blocker Evaluation of Survival Trial, I (2001) A trial of the

beta-blocker bucindolol in patients with advanced chronic heart

failure. N Engl J Med 344:1659–1667

174. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB,

Gilbert EM, Shusterman NH (1996) The effect of carvedilol on

morbidity and mortality in patients with chronic heart failure.

U.S. Carvedilol Heart Failure Study Group. N Engl J Med

334:1349–1355

175. van Veldhuisen DJ, Cohen-Solal A, Bohm M, Anker SD, Ba-

balis D, Roughton M, Coats AJ, Poole-Wilson PA, Flather MD,

Investigators S (2009) Beta-blockade with nebivolol in elderly

heart failure patients with impaired and preserved left ventric-

ular ejection fraction: data from SENIORS (Study of Effects of

Nebivolol Intervention on Outcomes and Rehospitalization in

Seniors With Heart Failure). J Am Coll Cardiol 53:2150–2158

176. Ceron CS, Rizzi E, Guimaraes DA, Martins-Oliveira A, Gerlach

RF, Tanus-Santos JE (2013) Nebivolol attenuates prooxidant

and profibrotic mechanisms involving TGF-beta and MMPs, and

decreases vascular remodeling in renovascular hypertension.

Free Radic Biol Med 65C:47–56

Heart Fail Rev

123