Hydrogen Sulfide Confers Cardioprotection Through Anti-inflammatory And Anti-apoptotic Effects In Myocardial Ischemia Injury

Part 1 Hydrogen Sulfide Confers Cardioprotection through Anti-inflammatory and Anti-apoptotic Effects in Acute Myocardial Ischemia InjuryBackgroundHydrogen sulfide (H2S), an endogenous signaling molecule, plays an important role in the physiology and pathophysiology of the cardiovascular system. Myeloid-derived suppressor cells (MDSCs) represent an intrinsic part of the myeloid-cell lineage and are a heterogeneous population of cells that expands during cancer, various infectious diseases, sepsis and trauma, and that has a remarkable ability to the negative regulation of immune responses. In mice, MDSCs are characterized by the co-expression of CD11b+ and Gr-1+. In the present study, we tried to investigate the role of CD11b+Gr-1+ myeloid cells after acute myocardial ischemia injury and the anti-inflammatory and anti-apoptotic effects of the H2S donor-sodium hydrosulfide (NaHS).Experimental approachUsing a mouse model of myocardial infarction (left coronary artery was permanent occluded), mice received 1 mg/kg NaHS (i.p.) or vehicle (normal saline) 5 min before surgery and 60 min after operation. We detected the survival, left ventricular function, myocardial infarct size, H2S levels in post-MI cardiac tissue, CD11b+Gr-1+ myeloid cells and cardiomyocyte apoptosis 24 h after MI.ResultsThe results demonstrated that the administration of NaHS improved survival, preserved left ventricular function, limited infarct size, and improved H2S levels in cardiac tissue to attenuate the recruitment of CD11b+Gr-1+ myeloid cells and regulate the Bax/Bcl-2 pathway. Furthermore, the cardioprotective effects of NaHS were enhanced by inhibiting the migration of CD11b+Gr-1+ myeloid cells from the spleen into the blood and by attenuating post-infarction inflammation. To systematically analyze the effect of H2S on inflammation, CDllb+Gr-1+ myeloid cells in blood and spleen were sorted for a gene profiling analysis. It appeared that a large number of genes associated with immune response, chemotaxis, and apoptosis were up-, or down-regulated by H2S in splenic CD11b+Gr-1+ myeloid cells.ConclusionsThese observations suggest that the novel mechanism underlying the cardioprotective function of H2S is secondary to a combination of anti-inflammatory and anti-apoptotic effects. The anti-inflammatory function may be in part due to the suppression of CD11b+Gr-1+ myeloid cells. The inhibition of cardiomyocyte apoptosis due to the regulation of Bax/Bcl-2 signaling pathway.Part 2 Effects of Hydrogen Sulfide in Postinfarction Cardiac RemodelingBackgroundThe innate immune system greatly contributes to the inflammatory process after myocardial infarction. CD11b+Gr-1+ myeloid cells, might has an essential role as a regulatory component of the innate immune response. The present study was hypothesized that H2S therapy impacts the cardiac inflammatory process, which consequently affects left ventricular remodeling after MI.Experimental approachMyocardial infarction was created in mice by left coronary ligation. Mice received 1 mg/kg NaHS (i.p.) or vehicle (normal saline) 5 min before surgery and 60 min after operation. We detected the survival, left ventricular function, viable myocardium, cardiac fibrosis, CD11b+Gr-1+ myeloid cells, apoptotic pathway and cardiac hypertrophy and pulmonary edema 1wk and/or 4 wk post-MI.ResultsDuring both the subacute and chronic stages (1 and 4 wk post-infarction, respectively), NaHS-treated mice demonstrated attenuated cardiac dilation, in the infarcted myocardium. Furthermore, NaHS-treated mice had fewer infiltration in peripheral circulation, infarct myocardium, and mobilization capacity of CD11b+Gr-1+ myeloid cells in splenic reservoir, attenuated the number of apoptotic cardiomyocytes, reduced interstitial fibrosis, ameliorated cardiac hypertrophy and pulmonary edema, and improved survival at 4 wk after MI.ConclusionsThese findings suggest that H2S protects against progression of postinfarction cardiac remodeling, may be in part due to a combination of anti-inflammatory (regulation of CD11b+Gr-1+ myeloid cells) and anti-apoptotic effects. Moreover, H2S could inhibit the cardiac fibrosis following myocardial ischemia through suppression the differentiation of cardiac fibroblasts into myofibroblasts in vivo.Part 3 Hydrogen Sulfide Suppresses Transforming Growth Factor-β1-Induced Differentiation of Human Cardiac Fibroblasts into MyofibroblastsBackgroundCardiac fibroblasts are the main source of cardiac fibrosis associated with cardiac hypertrophy and heart failure. Transforming growth factor-β1 (TGF-β1) irreversibly converts fibroblasts into pathological myofibroblasts, which characterized by expression of α-smooth muscle actin (a-SMA) and able to synthesize and secrete fibrillar collagen types Ⅰ and Ⅲ. The aim of the study was to investigate how H2S suppresses TGF-β1-stimulated conversion of fibroblasts to myofibroblasts.Experimental approachHuman cardiac fibroblasts were serum-starved in fibroblast media for 16 h before experiments. Cells were then stimulated with TGF-β1 (10 ng/ml) for 24 h to promote the cardiac myofibroblast phenotype in the absence or presence of NaHS (100 μM,30 min pretreatment).ResultsSodium hydrosulfide (NaHS) potently suppresses the cellular TGF-β1, inhibits the proliferation and migration, regulates cell cycle progress, suppresses the upregulates of the contractile marker a-SMA, differentiation of fibroblasts into myofibroblasts, and finally reduced the collagen levels in TGF-β1-induced human cardiac fibroblasts in vitro.ConclusionsH2S suppresses TGF-β1-stimulated conversion of fibroblasts to myofibroblasts by inhibiting the proliferation, migration, and regulating cell cycling progression. These results may be related to the reduction of cellular TGF-β1 secretion by NaHS.