GYY4137 attenuates remodeling, preserves cardiac function and modulates the natriuretic peptide response to ischemia. (October 2015)

• Record Type: Journal Article
• Authors: Lilyanna, Shera; Peh, Meng Teng; Liew, Oi Wah; Wang, Peipei; Moore, Philip K.; Richards, Arthur Mark; Martinez, Eliana C.
• Is Part Of: Journal of molecular and cellular cardiology. Volume 87(2015:Oct.)
• Page Start: 27
• Page End: 37
• Publication Date: 2015-10
• Subjects: ANP atrial natriuretic peptide -- BCL-2 B-cell CLL/lymphoma 2 -- BNP B-type natriuretic peptide -- cGKIα guanosine 3′5′-cyclic monophosphate-dependent kinase I alpha -- cGMP guanosine 3′5′-cyclic monophosphate -- CO cardiac output -- CSE cystathionine γ-lyase -- EF ejection fraction -- eNOS endothelial nitric oxide synthase -- GYY4137 morpholin-4-ium-4-methoxyphenyl (morpholino)phosphinodithioate salt -- FS fractional shortening -- H2S hydrogen sulfide -- IP intra-peritoneal -- LAD left anterior descending coronary artery -- LV left ventricular -- LVAWd left ventricular anterior wall in diastole -- LVAWs left ventricular anterior wall in systole -- LVEDP left ventricular end-diastolic pressure -- LVEDV left ventricular end-diastolic volume -- LVESV left ventricular end-systolic volume -- LVIDd left ventricular internal dimension in diastole -- LVIDs left ventricular internal dimension in systole -- MI myocardial infarction -- NaHS sodium hydrosulfide -- NPs natriuretic peptides -- NPR1 natriuretic peptide receptor 1 -- NPR3 natriuretic peptide receptor 3 -- PAG dl-propargylglycine -- p-eNOS phospho-endothelial nitric oxide synthase -- PRA plasma renin activity -- SC subcutaneous -- VEGF-A vascular endothelial growth factor-A; Hydrogen sulfide -- Natriuretic peptides -- Myocardial infarction -- Remodeling -- Angiogenesis; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2015.07.028
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Aims: Myocardial infarction followed by adverse left ventricular (LV) remodeling is the most frequent proximate cause of heart failure. Hydrogen sulfide (H2 S) is an important endogenous modulator of diverse physiological and pathophysiological processes. Its role in post-ischemic ventricular remodeling and the associated neurohormonal responses has not been defined. Here, we aimed at evaluating whether the slow-releasing water-soluble H2 S donor GYY4137 (GYY) exerts cardioprotective effects and modulates the neurohormonal response to cardiac ischemic injury. Methods and results: Treatment for 2 or 7 days with GYY (100 mg/Kg/48 h, IP) after acute myocardial infarction (MI) in rats preserved LV dimensions and function in vivo, compared to untreated infarcted (MI), placebo- anddl -propargylglycine- (PAG, an inhibitor of endogenous H2 S synthesis) treated animals (n = 9/group/time-point). LV dimensions and function in GYY-treated animals were comparable to healthy sham-operated rats. GYY-treated hearts had significantly less LV fibrosis than MI, placebo and PAG hearts. A higher density of blood vessels was found in the LV scar area of GYY-treated animals compared to all other infarcted groups. Despite preserved LV structure and function, treatment with GYY increased the levels of the natriuretic peptides ANP and BNP in association with enhanced cyclic GMP levels, paralleled by higher cGMP-dependent protein kinase type I (cGKI) protein levels. Conclusions: Our data suggest that the slow-releasing H2 S donor, GYY4137, preserves cardiac function, attenuates adverse remodeling and may exert post-ischemic cardioprotective (pro-angiogenic, anti-apoptotic, anti-hypertrophic and anti-fibrotic) effects in part through enhanced early post-ischemic endogenous natriuretic peptide activation. Highlights: Here, we assessed the role of H2 S in modulating neurohormonal responses to ischemic injury. We used the slow-releasing H2 S donor, GYY4137 (GYY), to treat rats after myocardial infarction. Treatment with GYY preserves cardiac function, reduces LV fibrosis and promotes angiogenesis. GYY may exert cardioprotective actions through natriuretic peptide activation.