Abstract 642: Upregulation of Heme Oxygenase Provides Vascular Protection in an Animal Model of Diabetes Through its Anti-Oxidant and Anti-Apoptotic Effects
Heme oxygenase (HO) plays a critical role in the regulation of cellular oxidative stress. The effects of the reactive oxygen species scavenger, Ebselen, and the HO inducers, CoPP and SnCl2, on HO protein levels and activity, indices of oxidative stress and the progression of diabetes were examined in the Zucker rat model of type 2 diabetes. The development of diabetes coincided with an increase in HO-1 protein despite a paradoxical decrease in HO activity. Diabetic rats also demonstrated increased expression of iNOS and decreased expression of eNOS. Administration of Ebselen, possibly through the removal of peroxynitrite, reduced HO-1 expression despite increasing HO activity in diabetic animals. In an in-vitro study, the addition of peroxynitrite resulted in nitration of immunoprecipitated HO-1 and decreased HO activity although a direct cause and effect for these findings has not been proven. Upregulation of HO-1 in the early development of diabetes produced a decrease in oxidative/nitrosative stress as manifested by decreased levels of 3-nitrotyrosine, superoxide and cellular heme content. This reduction in oxidative stress was accompanied by a decrease in endothelial cell sloughing, improved renal function and reduced blood pressure. Increased HO activity was also associated with a significant increase in the anti-apoptotic signaling molecules, Bcl-2, Bcl-xl and phosphorylation of p38-MAPK. In conclusion, 3-NT, cellular heme and superoxide, promoters of vascular damage, are reduced by HO-1 induction resulting in preserved vascular integrity through an increase in anti-apoptotic proteins. Restoration of endothelial function by HO induction restores renal function and attenuates hypertension demonstrating pharmacological potential in the fight against cardiovascular and renal disease.