Myocardial infarction is the most frequent proximate cause of heart failure, which remains a leading cause of death in the developed world. Hydrogen sulfide (H2S) is emerging as an important endogenous modulator in diverse physiological and pathophysiological events. We hypothesized that the slow-releasing water-soluble H2S donor GYY4137 (GYY) may exert cardioprotective effects through modulation of neurohormonal response to cardiac injury. We have found that treatment for 1 week with GYY (100mg/Kg/48hr, IP) after acute myocardial infarction in rats, provides powerful sustained preservation of left ventricular (LV) dimensions and function in vivo, compared to untreated infarcted (MI), placebo- and D-propargylglycine- (PAG, an inhibitor of endogenous H2S synthesis) treated animals 2 and 7 days after infarct (n=6/group/time-point). LV dimensions and function in GYY-treated animals were comparable to healthy sham-operated rats. GYY-treated hearts displayed a significantly lower percentage of LV fibrosis than MI, placebo and PAG hearts, whereas PAG treated animals had significantly bigger scar size relative to GYY, at days 2 and 7 after MI. A higher density of blood vessels was found in the scar area of GYY-treated animals compared to all other infarcted groups at days 2 (P<0.0002) and 7 (P<0.01) post-MI. Furthermore, treatment with GYY resulted in increased levels of plasma atrial natriuretic peptide (ANP) compared to all groups at days 2 and 7 after MI, while cardiac mRNA expression of ANP was also significantly increased in GYY-treated rats compared to Sham (P<0.001), and all the infarcted groups (P<0.05) at day 2 after MI. Concordantly, ANP second messenger cGMP was increased in plasma at day 7 in GYY rats compared to sham and all infarcted groups (p<0.05), paralleled by higher cGMP-dependent protein kinase type I (cGKI) protein levels than sham (P<0.01), and vasodilator-stimulated phosphoprotein phosphorylation (pVASP) at the cGKI preferred site (Ser239) compared to sham and PAG (P<0.05) at day 2 post-MI. In conclusion, our data suggest that H2S attenuates adverse remodeling and may exert post-ischemic cardioprotective (pro-angiogenic, anti-fibrotic) effects in part through modulation of ANP-mediated cGMP signal transduction.