Abstract
Hydrogen sulfide (H(2)S) is recognized as an endogenous gaseous signaling molecule generated by cystathionine γ-lyase (CSE) in cardiovascular tissues. H(2)S up-regulation has been shown to reduce ischemic injury, and H(2)S donors are cardioprotective in rodent models when administered concurrent with myocardial ischemia. We evaluated the potential utility of H(2)S therapy in ameliorating cardiac remodeling with administration delayed until 2 h post-infarction in mice with or without cystathionine γ-lyase gene deletion (CSE(-/-)). The slow-release H(2)S donor, GYY4137, was administered from 2 h after surgery and daily for 28 days following myocardial infarction (MI) induced by coronary artery ligation, comparing responses in CSE(-/-) with wild-type (WT) mice (n = 5-10/group/genotype). Measures of cardiac function and expression of key genes associated with cardiac hypertrophy, fibrosis, and apoptosis were documented in atria, ventricle, and kidney tissues. Post-MI GYY4137 administration reduced infarct area and restored cardiac function, accompanied by reduction of the elevated ventricular expression of genes mediating cardiac remodeling to near-normal levels. Few differences between WT and CSE(-/-) mice were observed, except CSE(-/-) mice had higher blood pressures, and higher atrial Mir21a expression across all treatment groups. These findings suggest endogenous CSE gene deletion does not substantially exacerbate the long-term response to MI. Moreover, the H(2)S donor GYY4137 administered after onset of MI preserves cardiac function and protects against adverse cardiac remodeling in both WT and CSE-deficient mice.