P54 Hydrogen sulfide inhibits activation of the renin-angiotensin system in diabetic heart

Abstract

Diabetic cardiomyopathy is a major contributing factor to morbidity in diabetics. A significant role of the cardiac renin-angiotensin system (RAS) in diabetic cardiomyopathy has been demonstrated clinically. Plasma levels of hydrogen sulfide (H 2 S), which have been demonstrated to inhibit plasma renin and endothelial ACE activity, are reduced in diabetic patients. The interaction between H 2 S and the RAS in the heart is unclear. We hypothesize that cardiac H 2 S levels are reduced in diabetes, resulting in cardiac RAS activation. Type 1 diabetes was induced in mice by streptozotocin. We observed that the expression of cystathionine gamma-lyase (CGL) in the heart was reduced significantly as diabetes progressed, whereas the cardiac RAS was activated. By using a fluorescent probe specific for H 2 S, we determined that H 2 S production was significantly impaired in neonatal rat ventricular myocytes (NRVM) cultured in high glucose medium (HG, 30 mM). In addition, DL-propargylglycine (PAG), a CGL inhibitor, increased the expression of angiotensinogen (AGT) in NRVM, suggesting that endogenous H 2 S is inhibitory to the cardiac RAS. HG significantly upregulated AGT expression in NRVM, which was further potentiated by PAG. GYY4137, a slow H 2 S releasing compound, completely abolished the effect of HG on RAS activation. Currently, we are using the transgenic mouse with cardiac specific over-expression of CGL to confirm these findings. In conclusion, downregulation of H 2 S synthesis may contribute to cardiac RAS activation in diabetes. Replenishing the H 2 S level in the diabetic heart, using an H 2 S donor, might provide a potential treatment for diabetic cardiomyopathy.