PL07 Diallyl trisulfide (DATS) protects against heart failure via eNOS activation and nitric oxide mediated cardioprotection

Abstract

Heart failure is the inability of the heart to meet hemodynamic demands and represents the end stage of various forms of cardiovascular disease. Current treatments for heart failure are inadequate and the availability of hearts for transplantation is extremely limited. Adjunctive therapies designed to coincide with the standard means of care are needed to slow the progression of adverse left ventricular remodeling during the development of heart failure. As the heart progresses rapidly from a compensated state to a state of decompensated failure, vascular growth cannot keep pace with myocyte growth. As such, therapies designed to induce angiogenesis or maintain coronary vascularity remain an attractive therapeutic option for the treatment of heart failure. Recent studies have shown that hydrogen sulfide (H 2 S) induces angiogenesis and promotes vessel growth in the setting of hind-limb ischemia. Here, we provide evidence that the administration of the stable, long-acting H 2 S donor, diallyl trisulfide (DATS), improves left ventricular remodeling and preserves left ventricular (LV) function in the setting of pressure-overload-induced heart failure. H 2 S therapy increased the expression of a number of pro-angiogenic factors, such as vascular endothelial cell growth factor, and Akt, the angiogenesis inhibitor, angiostatin. Importantly, these changes were associated with an increase in vascular density within the H 2 S-treated hearts. Additional studies demonstrated that H 2 S therapy resulted in activation of eNOS via phosphorylation of serine1177 with significant increases in (nitric oxide) NO bioavailability in the myocardium and circulation. These results suggest that H 2 S attenuates LV remodeling and dysfunction in the setting of heart failure by augmenting nitric oxide production via eNOS and creating a pro-angiogenic environment for the growth of new vessels.