Although many types of ancient bacteria and archea rely on hydrogen sulfide (H 2 S) for their energy production, eukaryotes generate ATP in an oxygen-dependent fashion. We hypothesize that endogenous H 2 S remains a regulator of energy production in mammalian cells under stress conditions, which enables the body to cope with energy demand when oxygen supply is insufficient. Cystathionine γ-lyase (CSE) is a major H 2 S-producing enzyme in the cardiovascular system that uses cysteine as the main substrate. Here we show that CSE is localized only in the cytosol, not in mitochondria, of vascular smooth-muscle cells (SMCs) under resting conditions, revealed by Western blot analysis and confocal microscopy of SMCs transfected with GFP-tagged CSE plasmid. After SMCs were exposed to A23187, thapsigargin, or tunicamycin, intracellular calcium level was increased, and CSE translocated from the cytosol to mitochondria. CSE was coimmunoprecipitated with translocase of the outer membrane 20 (Tom20) in mitochondrial membrane. Tom20 siRNA significantly inhibited mitochondrial translocation of CSE and mitochondrial H 2 S production. The cysteine level inside mitochondria is approximately three times that in the cytosol. Translocation of CSE to mitochondria metabolized cysteine, produced H 2 S inside mitochondria, and increased ATP production. Inhibition of CSE activity reversed A23187-stimulated mitochondrial ATP production. H 2 S improved mitochondrial ATP production in SMCs with hypoxia, which alone decreased ATP production. These results suggest that translocation of CSE to mitochondria on specific stress stimulations is a unique mechanism to promote H 2 S production inside mitochondria, which subsequently sustains mitochondrial ATP production under hypoxic conditions. mitochondrion | oxygen sensing | evolution | sulfur metabolism | phenylephrine M any photoautotrophic and chemoautotrophic bacteria and certain animals, such as the lugworm Arenicola marina, use sulfide as an energetic substrate. Mitochondria are the powerhouse of eukaryotic cells, where ATP is produced via oxidative phosphorylation. Considering mitochondria as the evolutionary trait of bacteria in eukaryotes, the metabolism of hydrogen sulfide (H 2 S) in mitochondria may serve as a means for energy supplementation. It has been demonstrated that H 2 S can drastically reduce metabolic demand (1). Similar to nitric oxide, H 2 S exerts protective effects on mitochondrial function and respiration (2). However, a conventional belief is that H 2 S is produced in the cytoplasm resulting from the cytosol localization of H 2 Sgenerating enzymes and is consumed through oxidation in mitochondria (3). It was recently demonstrated that mitochondria of human colon adenocarcinoma cells use sulfide as an energetic substrate at low micromolar concentrations, well below toxic levels (4). The foregoing observations call for reevaluation of the metabolism of H 2 S and its role in mitochondrial energization of eukaryotes. In the present study, we explored whether H 2 S can be prod...
A therosclerosis is characterized with plaque formation in large and medium-sized blood vessels. The stiffened and narrowed blood vessels limit blood circulation and increase plaque thrombogenicity, which threatens the functionality of vital organs such as the heart and brain. [1][2][3] The development of atherosclerosis is a chronic pathological process. Vascular remodeling and inflammation, endothelial dysfunction, smooth muscle cell (SMC) proliferation and migration, and accumulation of cholesterol-rich lipoproteins in blood vessel walls are early events of atherogenesis, resulting in the recruitment of circulating monocytes, their adhesion to endothelium via adhesion molecules, and their differentiation into macrophages. 4 The subendothelial accumulation of cholesterol-laden macrophages is morphologically recognized as foam cells. In humans, these fatty streaks can progress to more advanced lesions characterized by a lipid-rich necrotic core and a fibrous cap consisting of SMCs and collagen.Lesion rupture can result from the decreased viability of SMCs that is necessary for collagen production and for the structural integrity of the fibrous cap following the release of matrix metalloproteinases from apoptotic macrophages. 4-8 Editorial see p 2472 Clinical Perspective on p 2534Hydrogen sulfide (H 2 S), a member of the gasotransmitter family, plays a number of important physiological roles within the body, including protection against cardiovascular disease.9-11 Cystathionine γ-lyase (CSE) endogenously produces H 2 S in the cardiovascular system, 12,13 and the deficiency of CSE in mice leads to decreased endogenous H 2 S level, age-dependent increase in blood pressure, impaired endothelium-dependent vasorelaxation, and accumulation of homocysteine in the blood.14 Administration of NaHS (a H 2 S donor) protects rat aortic SMCs from the cytotoxicity caused Background-Cystathionine γ-lyase (CSE) produces hydrogen sulfide (H 2 S) in the cardiovascular system. The deficiency of CSE in mice leads to a decreased endogenous H 2 S level, an age-dependent increase in blood pressure, and impaired endothelium-dependent vasorelaxation. To date, there is no direct evidence for a causative role of altered metabolism of endogenous H 2 S in atherosclerosis development. Methods and Results-Six-week-old CSE gene knockout and wild-type mice were fed with either a control chow or atherogenic paigen-type diet for 12 weeks. Plasma lipid profile and homocysteine levels, blood pressure, oxidative stress, atherosclerotic lesion size in the aortic roots, cell proliferation, and adhesion molecule expression were then analyzed. CSE-knockout mice fed with atherogenic diet developed early fatty streak lesions in the aortic root, elevated plasma levels of cholesterol and low-density lipoprotein cholesterol, hyperhomocysteinemia, increased lesional oxidative stress and adhesion molecule expression, and enhanced aortic intimal proliferation. Treatment of CSE-knockout mice with NaHS, but not N-acetylcysteine or ezetimibe, inhibited the acceler...
The physiological and pathological roles of hydrogen sulfide (H2S) in the regulation of cardiovascular functions have been recognized. Cystathionine gamma-lyase (CSE) is a major H2S-producing enzyme in cardiovascular system. Ischemic post-conditioning (PC) provides cadioprotection in young hearts but lost in the aging hearts. The involvement of H2S in the recovery of PC-induced cardioprotection in the aging hearts is unclear. In the present study, we demonstrated that ischemia/reperfusion (I/R) decreased H2S production rate and CSE expression, aggravated cardiomyocytes damage, apoptosis and myocardial infarct size, reduced cardiac function, increased the levels of Bcl-2, caspase-3 and caspase-9 mRNA, enhanced oxidative stress in isolated young and aging rat hearts. I/R also increased the release of cytochrome c and down-regulated the phosphorylation of PI3K, Akt and GSK-3β in the aging rat hearts. We further found that PC increased H2S production rate and CSE expressions, and protected young hearts from I/R-induced cardiomyocytes damage, all of which were disappeared in the aging hearts. Supply of NaHS not only increased PC-induced cardioprotection in the young hearts, but also lightened I/R induced-myocardial damage and significantly recovered the cardioprotective role of PC against I/R induced myocardial damage in the aging hearts. LY294002 (a PI3K inhibitor) abolished but N-acetyl-cysteine (NAC, an inhibitor of reactive oxygen species, ROS) further enhanced the protective role of H2S against I/R induced myocardial damage in the aging hearts. In conclusion, these results demonstrate that exogenous H2S recovers PC-induced cardioprotection via inhibition of oxidative stress and up-regulation of PI3K-Akt-GSK-3β pathway in the aging rat hearts. These findings suggested that H2S might be a novel target for the treatment of aging cardiovascular diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s13578-015-0003-4) contains supplementary material, which is available to authorized users.
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.
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