S2-1 Hydrogen sulfide in heart failure

Abstract

Background Hydrogen sulfide (H2S) has been shown to induce angiogenesis in in vitro model systems and to promote vessel growth in the setting of chronic ischemia. The goal of the present study was to determine the therapeutic potential of a stable, long-acting H2S donors, SG-1002 and diallyl trisulfide (DATS), in a model of pressure-overload heart failure and to assess the effects of chronic H2S therapy on myocardial vascular density and angiogenesis. Studies were also performed to determine the mechanisms by which H2S protects the heart during heart failure. Methods and results Transverse aortic constriction was performed in mice (C57BL/6J; 8–10 weeks of age). Mice received either vehicle or diallyl trisulfide (200 μg/kg) or SG-1002 (20 mg/kg) starting 24 h after transverse aortic constriction and were followed for up to 12 weeks using echocardiography. H2S therapy with H2S donors significantly improved left ventricular remodeling and preserved left ventricular function in the setting of transverse aortic constriction. H2S therapy increased the expression of the proangiogenic factor, vascular endothelial cell growth factor, and decreased the angiogenesis inhibitor, angiostatin. Further studies revealed that H2S therapy increased the expression of the proliferation marker, Ki67, as well as increased the phosphorylation of endothelial NO synthase and the bioavailability of NO. Importantly, these changes were associated with an increase in vascular density within the H2S-treated hearts. In additional studies we determined that H2S therapy resulted in the activation of endothelial nitric oxide synthase (eNOS) via phosphorylation of serine1177 and increased nitric oxide (NO) bioavailability. Interestingly, we determined that eNOS was uncoupled in CSE KO mice with reduced levels of H2S and NO coupled with an exacerbated injury response to acute myocardial infarction. Conclusions These results suggest that H2S therapy attenuates left ventricular remodeling and dysfunction in the setting of heart failure by creating a proangiogenic environment for the growth of new vessels. A major mechanism related to these cytoprotective actions is the activation of eNOS and increased nitric oxide bioavailability.