AIM: Ischemic post-conditioning( PC) plays an important role in cardioprotection from ischemia / reperfusion( I / R) injury in the young heart but not in the aging hearts. The physiological and pathological roles of hydrogen sulfide( H_2S) in the regulation of cardiovascular functions have been recognized. Whether H_2 S is involved in the recovery of PC-induced cardioprotection in the aging hearts is unclear. METHOD: The male Wistar young rats( 3-month-old),the aging rats( 24-month-old),primary cultured cardiomyocytes and the aging cardiomyocytes induced by D-galactose suffered from I / R( or H / R) and PC. RESULTS: I / R( or H / R) decreased H_2 S production rate and cystathionine γ-lyase( CSE) expression,aggravated cardiomyocyte damage,apoptosis,myocardial infarct size and oxidative stress,reduced cardiac function,increased the levels of Bcl-2,cleaved caspase-3 and caspase-9 m RNA and proteins,promoted the release of cytochrome c and m PTP opening,down-regulated the phosphorylation of ERK1 /2,PI3 K,Akt and GSK-3β and mitochondrial membrane potential,up-regulated the phosphorylation of IκBɑ,NF-κB,JNK2 and STAT3,and inhibited PKC-ε translocation and mitochondrial ATP-sensitive K channels( mito K_(ATP)) in isolated young and aging hearts as well as normal and aging cardiomyocytes. PC suppressed myocardial I / R injury in the young heart but not in the aging hearts. Supply of Na HS not only increased PC-induced cardioprotection in the young hearts and cardiomyocytes,but also attenuated I / R injury and significantly recovered the cardioprotective role of PC in the aging hearts and cardiomyocytes. CONCLUSION: The exogenous H_2 S restores PC-induced cardioprotection through inhibiting oxidative stress via the down-regulation of NF-κB and JAK2-STAT3 pathways and m PTP opening by the up-regulation of ERK1 /2-GSK-3β,PI3K-Akt-GSK-3β and PKC-ε-mito K_(ATP) pathways in the aging hearts and cardiomyocytes. These findings provide a novel potential target for the treatment of aging ischemic cardiomyopathy. AIM: Ischemic post-conditioning (PC) plays an important role in cardioprotection from ischemia / reperfusion (I / R) injury in the young heart but not in the aging hearts. The physiological and pathological roles of hydrogen sulfide (H_2S) in the regulation Whether H_2 S is involved in the recovery of PC-induced cardioprotection in the aging hearts is unclear. METHOD: The male Wistar young rats (3-month-old), the aging rats (24-month- old primary cardiomyocytes and the aging cardiomyocytes induced by D-galactose suffered from I / R (or H / R) and PC. RESULTS: I / R (or H / R) decreased H_2S production rate and cystathionine γ-lyase (CSE) expression, aggravated cardiomyocyte damage, apoptosis, myocardial infarct size and oxidative stress, reduced cardiac function, increased the levels of Bcl-2, cleaved caspase-3 and caspase- 9 m RNA and proteins, promoted the release of cytochrome c and m PTP opening, down-regulated the phosphorylation of ERK1 / 2, PI3 K, Akt and GSK-3 β and mitochondrial membrane potential, up-regulated the phosphorylation of IκBɑ, NF- κB, JNK2 and STAT3, and inhibited PKC- ε translocation and mitochondrial ATP- sensitive K channels (ATP) in isolated young and aging hearts as well as normal cardiomyocytes. PC suppressed myocardial I / R injury in the young heart but not in the aging hearts. Supply of Na HS not only increased PC-induced cardioprotection in the young hearts and cardiomyocytes, but also attenuated I / R injury and significantly recovered the cardioprotective role of PC in the aging hearts and cardiomyocytes. CONCLUSION: The exogenous H_2 S restores PC-induced cardioprotection through inhibiting oxidative stress via the down-regulation of NF-κB and JAK2-STAT3 pathways and m PTP opening by the up-regulation of ERK1 / 2-GSK-3β, PI3K-Akt-GSK-3β and PKC-ε-mito K (ATP) pathways in the aging hearts and cardiomyocytes. provide a novel potential target for the treat ment of aging ischemic cardiomyopathy.