Exogenous hydrogen sulfide restores cardioprotection of ischemic post-conditioning via inhibition of mPTP opening in the aging cardiomyocytes

Abstract

The physiological and pathological roles of hydrogen sulfide (H2S) in the regulation of cardiovascular functions have been recognized. H2S protects against the hypoxia/reoxygenation (H/R)-induced injury and apoptosis of cardiomyocytes, and ischemic post-conditioning (PC) plays an important role in cardioprotection from H/R injury in neonatal cardiomyocytes but not in aging cardiomyocytes. Whether H2S is involved in the recovery of PC-induced cardioprotection in aging cardiomyocytes is unclear. In the present study, we found that both H/R and PC decreased cystathionine-γ-lyase (CSE) expression and the production rate of H2S. Supplementation of NaHS protected against H/R-induced apoptosis, the expression of cleaved caspase-3 and cleaved caspase-9, the release of cytochrome c (Cyt c), and mPTP opening. The addition of NaHS also counteracted the reduction of cell viability caused by H/R and increased the phosphorylation of ERK1/2, PI3K, Akt, GSK-3β and mitochondrial membrane potential. Additionally, NaHS increased Bcl-2 expression, promoted PKC-ε translocation to the cell membrane, and activated mitochondrial ATP-sensitive K channels (mitoKATP). PC alone did not provide cardioprotection in H/R-treated aging cardiomyocytes, which was significantly restored by the supplementation of NaHS. In conclusion, our results suggest that exogenous H2S restores PC-induced cardioprotection via the inhibition of mPTP opening by the activation of the ERK1/2-GSK-3β, PI3K-Akt-GSK-3β and PKC-ε-mitoKATP pathways in aging cardiomyocytes. These findings provide a novel target for the treatment of aging ischemic cardiomyopathy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13578-015-0035-9) contains supplementary material, which is available to authorized users.

Ischemic Postconditioning Alleviates Intestinal Ischemia-Reperfusion Injury by Enhancing Autophagy and Suppressing Oxidative Stress through the Akt/GSK-3β/Nrf2 Pathway in Mice

“…This endogenous protective-adaptive intervention suppresses spontaneous Ca 2+ oscillations and inhibits mPTP opening [22], contributing to the maintenance of mitochondrial homeostasis, attenuation of oxidative stress, and alleviation of apoptosis [23]. IPO-induced protection against IR injury has been confirmed in multiple organs [11,19,22]. Consistent with these studies, we found that IPO markedly attenuated IIR injury as characterized by reduced histological damage and lower levels of serum biomarkers.…”

“…IPO is defined as rapid intermittent interruptions of blood flow in the early phase of reperfusion that mechanically alter the hydrodynamics of reperfusion. This endogenous protective-adaptive intervention suppresses spontaneous Ca 2+ oscillations and inhibits mPTP opening [22], contributing to the maintenance of mitochondrial homeostasis, attenuation of oxidative stress, and alleviation of apoptosis [23]. IPO-induced protection against IR injury has been confirmed in multiple organs [11,19,22].…”

The path from mitochondrial ROS to aging runs through the mitochondrial permeability transition pore

“…Because aging in general decreases antiapoptotic pathways and increases pro‐apoptotic pathways, other mitochondrial proteins that are known to inhibit mPTP are probably also reduced by aging; these may include HSP75 (Wang et al ., ), HSP60 and HSP90 (TRAP1; Altieri, ), which are induced by the UPR(mt), and antiapoptotic proteins, such as BCL‐2 and BCL‐x L (Jonas et al ., ). Moreover, an increasing number of metabolites were reported to control the mPTP directly or indirectly, for example, mitochondrial cAMP and cyclic nucleotide phosphodiesterase (CNP; Baburina et al ., ), polyphosphate (Baev et al ., ), spermine (Wei et al ., ), and H 2 S (Li et al ., ). These effects are probably also modulated by aging.…”

“…A recent study on lifespan extension in C. elegans by germline loss shows that lifespan extension in this case depends on two independent pathways, one of which is mROS dependent (UPRmt) and the other not (the H 2 S pathway; Wei & Kenyon, ). However, H 2 S, similar to UPRmt, also inhibits the mPTP (Li et al ., ). In a study of a very large number of C. elegans lifespan modulations by mutations and environmental manipulations, it was shown that lifespan correlates negatively with the frequency of ‘mitoflashes’ at an early adult age (Shen et al ., ).…”

Heat shock factor 1-mediated transcription activation of Omi/HtrA2 induces myocardial mitochondrial apoptosis in the aging heart

“…Several studies have indicated that the mitochondriadependent apoptosis signaling pathway is more active in multiple organs of the elderly, for instance, muscle [18], heart [19]. Our previous study showed that the increased expression of Omi (also known as HtrA2) enhances MI/R injury in aged hearts [9] by inducing myocardial mitochondrial apoptosis [11].…”