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Hydrogen sulfie donor, GYY4137, exhibits anti-atherosclerotic activity in high fat fed apolipoprotein E knockout mice
Prof. Yong Ji, Ph.D., M.D
Atherosclerosis Research Center
Nanjing Medical University
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Ross R. N Engl J Med. 1999.
These risk factors most frequently include hypertension, tobacco smoking, diabetes mellitus, obesity, and genetic predisposition; the molecular details of how they work are not yet known.
Atherosclerosis
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John W.etal. Antioxid. Redox Signal. 2009.
Endogenously produced gases
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John W. et al. Antioxid. Redox Signal. 2009.
Cardiovascular actions of hydrogen Sulfide
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Cardiovascular actions of hydrogen Sulfide
Elsey DJ. et al. Cell Biochem Funct 2010.
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CBS
H2S
Pyridoxal-5’-phosphate
H2SH2S
John W. et al. Antioxid. Redox Signal. 2009.
3-MST CSE
L-cysteine3-mercaptopyruvate
neurons astrocytes
Biosynthesis of H2S
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Role of Hydrogen Sulfide in the Development of Atherosclerotic Lesions in Apolipoprotein
E Knockout Mice
Wang Y, et al. Arterioscler Thromb Vasc Biol 2009.
H2S and Atherosclerosis
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ACS14 may prevent the progression of atherosclerosis by downregulating macrophage CX3CR1 expression.
H2S and Atherosclerosis
Zhang H, et al. Eur J Pharmacol 2012.
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H2S and Atherosclerosis
H2S inhibited atherogenic modification of purified LDL induced by hypochlorite
H2S induced apoptosis of human aorta smooth muscle cells.
H2S inhibit homocysteine-induced superoxide production in rat thoracic aortic smooth muscle cells.
H2S inhibit adhesion to TNF-α-activated HUVEC.
Yang G. et al. FASEB J. 2004.
Yan et al. BBRC. 2006.
Lagger et al. Free Radic Res. 2007
Pan LL, et al. Plos one 2011.
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Controversial findings
H2S induces proinflammatory cytokines synthesis in human monocyte cell line.
H2S regulates leukocyte trafficking in cecal ligation and
puncture-induced sepsis.
Zhang H et al.J Leukoc Biol. 2007.
Zhi L, et al. J Leukoc Biol. 2007.
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Limitations
In aqueous solution, NaHS releases large amount of H2S over a period of a few seconds.
Nevertheless, this salt gives poor satisfaction for clinical uses , because the rapid release of H2S may cause adverse effects, such as acute and excessive lowering of blood pressure.
Ideal H2S-donors for therapeutic purposes should generate H2S with slow releasing rates.
Notably, considerable emphasis has also been placed on the use of NaHS as a “tool” to model the biological effects of endogenous H2S.
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Characterization of a Novel, Water-Soluble Hydrogen Sulfide Releasing Molecule
(GYY4137): New Insights Into the Biology of Hydrogen Sulfide
Li L, et al. Circulation. 2008.
GYY4137
GYY4137
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NaHS GYY4137
Li L et al. Circulation. 2008.
GYY4137 and NaHS
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Li L et al. Free Radic Biol Med, 2009.
0-1000umol/L
Anti-inflammation
Macrophages
LPS
GYY4137
NaHS Inflammation
Effect of hydrogen sulfide donors on LPS-induced formation of inflammatory mediators in macrophages
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AS
Oxide stress Inflammation Endothelial dysfunction
Hypothesis
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GYY4137 inhibited lipid accumulation and experssion of LOX-1 protein induced by Ox-LDL in RAW264.7 Cells
A
B
C
*P <0.05,***P < 0.001 vs CTL ; #P<0.05, ##P<0.01vs ox-LDL treated group. n=4
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Effects of GYY4137 on H2S system in RAW264.7 Cells
A B
+P<0.05, c.f. no treatment, *P<0.05, c.f. treatment with oxLDL. n=4
?
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ZYJ1122, a structural analogue of GYY4137
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ZYJ1122, a structural analogue of GYY4137 , is unable to release H2S or affect lipid accumulation in RAW264.7 Cells
BC
+P<0.05, c.f. no treatment, n=4
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ZYJ1122, a structural analogue of GYY4137 , is unable to release H2S or affect lipid accumulation in RAW264.7 Cells
A B
C
+P<0.05, c.f. control, n=4
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ZYJ1122, a structural analogue of GYY4137 , is unable to inhibit lipid accumulation in in RAW264.7 Cells
A
B
C
+P<0.05, c.f. no treatment, *P<0.05, c.f. treatment with ox-LDL.n=4-6
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GYY4137, but not ZYJ1122, inhibited lipid accumulation in human peripheral blood moncyte-derived macrophages
*P <0.05, **P<0.01 vs CTL ; #P<0.05vs GYY4137.n=6-9.
healthy donors. patient with coronary heart disease.
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GYY4137 inhibited chemokine releasing in ox-LDL-treated RAW 264.7 cells
CXCL2 CXCL10 CXCR-4
+P<0.05, c.f. no treatment, *P<0.05, c.f. treatment with oxLDL.n=4-6
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GYY4137 prevented ox-LDL induced macrophage iNOS expression
A B
+P<0.05, c.f. no treatment, *P<0.05, c.f. treatment with oxLDL.n=4
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GYY4137 prevented oxLDL-induced macrophage NF-κB activation
A B C
D E
*P <0.05, ,**P < 0.01, ***P < 0.001 vs no treatment ; #P<0.05, ##P<0.01 ###P<0.001vs ox-LDL treated group
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GYY4137 prevented oxLDL-induced macrophage ICAM-1 and VCAM-1 Experssion
+P<0.05, c.f. no treatment, *P<0.05, c.f. treatment with oxLDL.n=4
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Eight-week-old
ApoE-/- mice
High-fat diet
for four weeks
Oil-red O–stained aortic root lesions of mice
Normal food for 30days
GYY4137( 50mg/kg body weight ) or NS, (i.p. )
Anesthetized and sacrificed .
Animal experiment
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Effects of GYY4137 on H2S system in apoE-/- mice
‡ P<0.05, c.f. WT mice, §P<0.05, c.f. ApoE-/- + NS 。( n=5-8 )
A B
?
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GYY4137 has no effect on body weight and plasma lipids
TC:total cholesterol, TG:triglyceride, HDL-C: high-density lipoprotein-cholesterol, LDL-C: low-density lipoprotein-cholesterol. *P < 0.05, **P < 0.01, ***P < 0.001 vs WT. n=5-8 animals/group.
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GYY4137 decreases atherosclerotic lesion size in apoE-/- mice
A B
**P < 0.01, ***P < 0.001 vs WT, ###P < 0.01 vs apoE-/- + NS. n=5-8 animals/group.
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GYY4137 improved endothelium-dependent relaxation function and activated PI3K/Akt/eNOS Pathway
A B
C D
*P < 0.05, ***P < 0.001 vs WT. #P < 0.05, ##P < 0.01,vs apoE-/- + NS. n=6 animals/group.
?
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GYY4137 reduced superoxide formation and LOX-1 expression in aortas of apoE-/- mice
A a b
B
**P < 0.01 vs WT mice. #P < 0.05 vs apoE-/- + NS. n=6 animals/group.
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GYY4137 reduced TNF-α, IL-6 and ICAM-1 mRNA expression in aortas of apoE-/- mice
**P < 0.01 vs WT mice. #P < 0.05 vs apoE-/- + NS. n=6 animals/group.
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Summary
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