aerobic training induces lvh involving micrornasedilamar menezes de oliveira [email protected] grant...
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Aerobic training induces LVH involving
microRNAs
Edilamar Menezes de Oliveira [email protected]
Grant FAPESP (2009/18370-3)
Grant CNPq/MCT-2009
Laboratory of Biochemistry and Molecular Biology of the Exercise
School of Physical Education and Sport
University of Sao Paulo - Brazil
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Morfológicas/Funcionais
Diretriz de Reabilitação Cardíaca, SBC, 2005 Oliveira & Krieger, 2002
Rno-mir-1
Hemodinâmicas
PA de repouso Fluxo Sanguíneo Volume plasmático
Cardiovasculares
FC repouso Melhor Função Ventricular (VS) Angiogênese
HIPERTROFIA
CARDÍACA FISIOLÓGICA
Metabólicas VO2max Estrutura miofibrilar Síntese e atividade enzimática
Adaptações Fisiológicas ao Treinamento Físico Aeróbio
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Fernandes T et al. BJMBR, Sep, 2011
Nadal-Ginard & Madavi, J Clin Invest, 1989.
Heineke & Molkentin Nat Rev, 2006.
Physiological Cardiac Hypertrophy
RV LVRV LVLVRV
SEDENTARY
Eccentric Hypertrophy
AEROBIC TRAINING RESISTANCE TRAINING
Concentric HypertrophyVolume overload
Chamber dilation
Myocyte length >> Myocyte width
No fibrosis
No cardiac dysfunction
Pressure overload
Without chamber dilation
Myocyte width >> Myocyte length
No fibrosis
No cardiac dysfunction
sarcomeres
RV LVRV LVRV LVRV LVLVLVRV LVRV
SEDENTARY
Eccentric Hypertrophy
AEROBIC TRAINING RESISTANCE TRAINING
Concentric HypertrophyVolume overload
Chamber dilation
Myocyte length >> Myocyte width
No fibrosis
No cardiac dysfunction
Pressure overload
Without chamber dilation
Myocyte width >> Myocyte length
No fibrosis
No cardiac dysfunction
sarcomeres
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DORN, Hypertension , 2007.
INFLAMA Ç Ã O
APOPTOSE
GLIC Ó LISE
GENES FETAIS
S Í NTESE DE
PROTE Í NA
MATRIX
EXTRACELULAR
BIOG Ê NESE
MITOCONDRIA
METABOLISMO
OXIDATIVO
CAPILARIZA ÇÃ O
HIPERTROFIA DE
CARDIOMI Ó CITOS
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Some miRNAs are specifically expressed in specific
tissues, such as heart
MicroRNAs are short sequences
non coding protein
regulate specific target genes by
inhibiting translation
MicroRNAs
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Descoberta
Lee RC, Feinbaum RL, Ambros V. Cell,1993.
Victor Ambros
Rosalind Lee
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Descoberta
Reinhart, B. et al. Nature , 2000.
Lin-14
Lin-28
Lin-41
Lin-42
Daf-12
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Descoberta em Humano
Pasquinelli, AE. et al. Nature , 2000.
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2002
– Correlation between miRNAs e Câncer
2005
– Dicer deletion indicating miRNA relevance in
diferent model systems
- Antagomir inhibition of mRNAs in vivo
- First miRNA transgênic mouse
2006 - Correlation between miRNAs and CV disease
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MicroRNAs e HC
Van Rooij E. et al. Proc Natl Acad Sci U S A. 2006 .
Eva van Rooij
Eric Olson
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Humano
21
7
Constrição aórtica
Knock in Caucineurina A
Van Rooij E. et al. Proc Natl Acad Sci U S A. 2006 .
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Care A. et al. Nature Medicine, 2007.
Gianluigi Condorelli
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Van Rooij E. et al. Science, 2007.
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O Exercício Físico poderia influenciar na expressão de microRNAs no remodelamento
cardíaco?
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We investigate the role of microRNAs
regulating LV hypertrophy induced by aerobic
training in normotensive rats:
- Classic and the novel cardiac renin angiotensin
system (RAS);
- Angiogenesis;
- Collagen.
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Training Protocols
Swimming training 1 (T1): 60 min/day;
1x day;
5x/week;
during 10 weeks
Swimming training 2 (T2): 60 min/day;
1x/ day;
5x/week;
during 8 weeks
9a week: 60 min; 5x/week; 2x/ day
10a week: 60 min; 5x/week; 3x/ day
Oliveira et al., JRAAS, 2009.
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Training Protocols
Swimming training 1 (T1): 60 min/day;
1x day;
5x/week;
during 10 weeks
Swimming training 2 (T2): 60 min/day;
1x/ day;
5x/week;
during 8 weeks
9a week: 60 min; 5x/week; 2x/ day
10a week: 60 min; 5x/week; 3x/ day
Oliveira et al., JRAAS, 2009.
Moderate-volume training Moderate Cardiac Hypertrophy
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Training Protocols
Swimming training 1 (T1): 60 min/day;
1x day;
5x/week;
during 10 weeks
Swimming training 2 (T2): 60 min/day;
1x/ day;
5x/week;
during 8 weeks
9a week: 60 min; 5x/week; 2x/ day
10a week: 60 min; 5x/week; 3x/ day
Oliveira et al., JRAAS, 2009.
Moderate-volume training Moderate Cardiac Hypertrophy
High-volume training Robust Cardiac Hypertrophy
High performance, like an atleta
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Oliveira et al., JRAAS, 2009.
Swimming training System
Workload: caudal dumbbells weighting 5% of corresponding body
weight
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Exercise training markers
* p<0.05, vs SC. Soci, UPR et al., Physiological Genomics 43: 665-673, 2011
Fernandes, et al., Hypertension, 58: 182-189, 2011
Heart rate
SC T1 T2
*
*
0
150
300
450
600
S T1 T2
Citrate synthase activity
SC
T1
T2
* *
SC T1 T2
CS
act
ivit
y
(µm
ol/
ml/
mg
pro
tein
)
Cardiovascular Marker
Metabolic Marker
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A CB C T1 T2
0
30
60
90
120
150
ECO (mg/g) LV/BW (mg/g) Myocyte Diameter (µm)
Card
iac
Hyp
ert
rop
hy
(% o
f c
on
tro
l) *
* * **
** *
† S T1 T2
S T1 T2
Cardiac Hypertrophy
Soci, UPR et al., Physiological Genomics 43: 665-673, 2011
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y = 17,26x + 25,48
R = 0.680018
P<0.05
55
65
75
85
95
2.3 2.5 2.7 2.9 3.1 3.3 3.5
VO
2m
ax
(m
l.k
g-1
.min
-1 )
Cardiac Hypertrophy
(mg/g)
Positive Correlation
VO2max X Cardiac Hypertrophy
Soci, UPR et al., Physiological Genomics 43: 665-673, 2011
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p<0.05 vs SC
Pathological Cardiac Hypertrophy Markers
Soci, UPR et al., Physiological Genomics 43: 665-673, 2011
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microRNA Array (349 miRNAs)
87 microRNAs were
differentially expressed with
exercise training
- 10.000 20.000 30.000 40.000 50.000 60.000
miRNA
- 2.000 4.000 6.000 8.000 10.000
miRNA
P2 P1 SC
* p<0.01 vs SC.
T2
T1
SC
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miRNAs differentially expressed in the
LV with Exercise training.
Increased by T1
SC
Decreased by T1
Largest decreased by T2
Largest increased by T2
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miRs, 1, 133a e 133b Expression
* p<0.01 vs SC. Soci, UPR et al., Physiological Genomics 43: 665-673, 2011
0
10000
20000
30000
40000
50000
60000
70000
1
Un
ida
de
s a
rbit
rári
as
de
ex
pre
ss
ão
gê
nic
a
SC
P1
P2
miR-133a miR-133b miR-1
m
iRN
As L
evels
(U
.A.)
T1
T2
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We investigate the role of microRNAs
regulating LV hypertrophy induced by aerobic
training in normotensive rats:
- Classic and the novel cardiac renin angiotensin
system (RAS);
- Angiogenesis;
- Collagen.
![Page 38: Aerobic training induces LVH involving microRNAsEdilamar Menezes de Oliveira edilamar@usp.br Grant FAPESP (2009/18370-3) Grant CNPq/MCT-2009 Laboratory of Biochemistry and Molecular](https://reader036.vdocuments.net/reader036/viewer/2022071406/60fc0b11d8662d63c8451f74/html5/thumbnails/38.jpg)
Fernandes, et al., Hypertension, 58: 182-189, 2011
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Fernandes, et al., Hypertension, 58: 182-189, 2011
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Fernandes, et al., Hypertension, 58: 182-189, 2011
Cardiac ACE - Ang II axis
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Cardiac ACE-2 - Ang (1-7) axis
Fernandes, et al., Hypertension, 58: 182-189, 2011
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Cardiac ACE-2 - Ang (1-7) axis
Fernandes, et al., Hypertension, 58: 182-189, 2011
These results suggest that this nonclassic cardiac RAS
counteracts the classic RAS
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Fernandes, et al., Hypertension, 58: 182-189, 2011
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This modulation might increase blood and oxygen transport to the
exercising cardiac muscle to facilitate high performance
miR-143
VASODILATION
VASOCONSTRICTION
ACE-2
CH
miR-27a
miR-27b
ACE
microRNA and
Physiological Hypertrophy
Ang (1-7)
Ang II
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We investigate the role of microRNAs
regulating LV hypertrophy induced by aerobic
training in normotensive rats:
- Classic and the novel cardiac renin angiotensin
system (RAS);
- Angiogenesis;
- Collagen.
![Page 46: Aerobic training induces LVH involving microRNAsEdilamar Menezes de Oliveira edilamar@usp.br Grant FAPESP (2009/18370-3) Grant CNPq/MCT-2009 Laboratory of Biochemistry and Molecular](https://reader036.vdocuments.net/reader036/viewer/2022071406/60fc0b11d8662d63c8451f74/html5/thumbnails/46.jpg)
- 5.000 10.000 15.000 20.000 25.000
rno-let-7f
rno-miR-126
rno-let-7b
rno-miR-221
rno-miR-222
rno-miR-27b
rno-miR-378
rno-miR-214
Expressão gênica (Unidades Arbitrárias)
SC
P1
P2
microRNAs Angiogênicos
Silva-Jr ND et al., Medicine & Science in Sports & Exercise (em revisão)
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Representação esquemática da ação do miR-126 em vias angiogênicas mediadas por VEGF
Silva-Jr ND et al., Medicine & Science in Sports & Exercise (em revisão)
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0
50
100
150
200
250
SC P1 P2
*
*
†
SC
P1
P2
Exp
ress
ão r
elati
va d
o V
EG
F n
o V
E
por
wes
tern
blo
ttin
g(%
do c
on
trole
)
microRNA e Angiogênese Cardíaca
Silva-Jr ND et al., Medicine & Science in Sports & Exercise (em revisão)
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microRNA-126 no VE
0
20
40
60
80
100
120
140
160
180
200
SC P1 P2
Exp
ressão r
ela
tiva d
o m
iR-1
26 n
o V
Ep
or m
icro
arra
y(%
do
co
ntr
ole
) ******† † †
A
0
20
40
60
80
100
120
140
160
SC P1 P2
po
r r
ea
l-ti
me P
CR
(%
do
co
ntr
ole
)
Ex
pressã
o r
ela
tiv
a d
o m
iR-1
26
no
VE
***
SC
P1
P2
B
0,4
0,6
0,8
1,0
1,2
1,4
1,6
0,0 0,5 1,0 1,5 2,0 2,5m
iR-1
26 (
2 -
Ct )
Razão capilar / fibra no VE(no capilares / fibra)
R = 0,63
P < 0,05
Silva-Jr ND et al., Medicine & Science in Sports & Exercise (em revisão)
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Representação esquemática da ação do miR-126 em vias angiogênicas mediadas por VEGF
0
20
40
60
80
100
120
SC P1 P2
Exp
ress
ão r
ela
tiva d
o P
I3K
R2 n
o V
E
por r
eal
tim
e –
PC
R (
% d
o c
on
trole
)
SC
P1
P2
*
*** †
0
20
40
60
80
100
120
SC P1 P2
SC
P1
P2
* *E
xp
ress
ão
rela
tiv
a d
o S
pred
-1 n
o V
E
po
r w
est
ern
blo
ttin
g(%
do
co
ntr
ole
)
Silva-Jr ND et al., Medicine & Science in Sports & Exercise (em revisão)
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miR-126
VEGF
VEGFR2
PI3K
Akt
eNOS
Raf-1
MEK 1/2
PI3KR2 Spred-1
miR-126
ERK 1/2
Treinamento
de Natação
ANGIOGÊNESE CARDÍACA
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We investigate the role of microRNAs
regulating LV hypertrophy induced by aerobic
training in normotensive rats:
- Classic and the novel cardiac renin angiotensin
system (RAS);
- Angiogenesis;
- Collagen.
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Soci, UPR et al., Physiological Genomics 43: 665-673, 2011
miR-29 Family
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MicroRNAs 29a, b e c:
Cardiac Fibrosis Target Genes
Van Rooij et al, PNAS, 2008
Target Genes Validated
COL1 A1
COL1 A2
COL3 A1
ELN
FBN1
MicroRNA 29
Collagen Fibrilin Elastin
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miRNA-1 miRNA-133a miRNA-133b miRNA-29c 0
50
100
150
200
250
300
* * * * * *
*
* S
T1
T2
S
T1
T2
Rela
tive
LV
miR
NA
s l
eve
ls
by r
ea
l-ti
me
PC
R (
% o
f c
on
tro
l)
miRNAs Expression by Real Time-PCR
* p<0.05, vs. S
Soci, UPR et al., Physiological Genomics 43: 665-673, 2011
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Collagen Expression
* p<0.05 vs. S
0
25
50
75
100
125
COLIAI COLIIIAI
Re
lati
ve E
xpre
ssio
n o
f LV
Co
llage
n(%
of
con
tro
l)
S
T1
T2
*
**
40% 49% 61% 52%
*
Soci, UPR et al., Physiological Genomics 43: 665-673, 2011
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Cardiac Collagen Concentration and miRNA-29
0
70
140
210
280
S T1 T2
LV
mic
roR
NA
-29c le
vels
(%
of
co
ntr
ol)
MiRNA29c
*
*
Soci, UPR et al., Physiological Genomics 43: 665-673, 2011
0
30
60
90
120
150
S T1 T2
Car
dia
c O
H-P
rolin
(m
g/g)
(% o
f c
on
tro
l) * *
Colágeno cardíaco Cardiac Collagen
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miRNA-29 Expression was inversaly correlated to
OH-Proline concentration in the heart
MiRNA- 29c (2 -ΔΔCT)
0
100
200
300
1 2 3
OH
-pro
lin
e (
mg
/g)
R = -0.61
P<0.05
0
Soci, UPR et al., Physiological Genomics 43: 665-673, 2011
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The collagen concentration decreased
was associated with improvement of
ventricular compliance and function
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Physiological Genomics 43: 665-673, 2011
SC (n=7)
T1 (n=6)
T2 (n=6)
Systolic Function
EFj (%)
77±5
75±2
73±2
EFn (%)
39±4
38±3
36±2
VEC (circ/s)
0.005±0.02
0.004±0.2
0.004±0.04
Diastolic Fuction
Peak E (m/s)
0.451±0.05
0.499±0.05
0.458±0.03
Peak A (m/s)
0.328±0.06
0.333±0.03
0.279±0.01
Ratio E/A
1.396±0.16
1.504±0.19
1.644±0.11*
IVRT(ms)
30.2±1.7
27.0±1.8*
* p<0.05, vs. S
Echocardiography
30.7±1.9
Global Function
DTPE (ms)
2.2±0.2 1.8±0.1* 1.9±0.2*
MPI
0.51±0.06 0.35±0.09* 0.38±0.07*
IVRT: isovolumetric relaxation time;
DTPE: deceleration time of peak E;
MPI: Myocardial Performance Index
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Soci, UPR et al., Physiological Genomics 43: 665-673, 2011
Summary
ET
Diastolic Function
COLI and COLIII Expression Cardiac COL Concentration Pathological Cardiac Markers
miR-29c
Physiological
Cardiac Hypertrophy
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Fernandes T et al. BJMBR, 2011.
AEROBIC TRAINING
miR-1, 133a and 133b miR-29a, 29b and 29c miR-27a and 27b miR-143
Rhoa/ CDC42
NELFA/ Whsc2
COLIAI
COLIIIAI
ACE ACE2
LV
PHYSIOLOGICAL
CARDIAC
HYPERTROPHY
Differentiation
and growth cell
Ventricle
Compliance
Vasodilation
Anti-fibrosis
Vasodilation
Anti-fibrosis
AEROBIC TRAINING
miR-1, 133a and 133b miR-29a, 29b and 29c miR-27a and 27b miR-143
Rhoa/ CDC42
NELFA/ Whsc2
COLIAI
COLIIIAI
ACE ACE2
LVLV
PHYSIOLOGICAL
CARDIAC
HYPERTROPHY
Differentiation
and growth cell
Ventricle
Compliance
Vasodilation
Anti-fibrosis
Vasodilation
Anti-fibrosis
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Together these effects induce regulation of
cardioprotector genes, improve ventricular
compliance, and might provide the additional aerobic
capacity required by the exercised heart.
These results suggests that a basis for treatment to
prevent of the development of pathological LVH
might be to inhibit specific miRNAs, using antisense
or siRNA.
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Perspectivas Futuras
Estudos com Animais Experimentais:
-SHR - Bolsa de Mestrado (FAPESP (Projeto 2009/03264-3)
-Insuficiência cardíaca – Bolsa de Doutorado (FAPESP (Projeto 2010/09438-0)
Estudo com Humanos: (Colaboração com Prof. Carlos Eduardo Negrão e Profa.
Maria Urbana Rondon).
-Pacientes Hipertensos
-Pacientes Resincronizados
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Acknowledgments Pos-graduation Students
Tiago Fernandes
Ursula Soci
Marco Amadeu
Nara Hashimoto
Flávio Magalhães
Kaleizu Rosa -InCor
Colaborations:
Prof. Maria Cláudia Irigoyen and José Eduardo Krieger – InCor
Prof. Adriana Carmona and Dulce Casarini - UNIFESP
Dr. M Ian Phillips – KGI –California – USA.
Laboratory Technician
Glória Motta
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Laboratory of Biochemistry and Molecular Biology of the Exercise
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Thank you for your attention