Abstract 1158: Nox4 Mediates Cardiomyopathy Phenotype in Diabetes
Cardiomyopathy is a common complication of type 1 and type 2 diabetes. Diabetic cardiomyopathy is characterized by myocyte hypertrophy, interstitial fibrosis and impaired left ventricular function. Oxidative stress has been implicated in the pathogenesis of diabetic complications. We investigated the role of the NADPH oxidase Nox4 as a source of reactive oxygen species (ROS) that contribute to cardiomyopathy phenotype in a rat model of type 1 diabetes induced by streptozotocin. Phosphorothioated antisense (AS) or sense oligonucleotides (S) for Nox4 were administered for 2 weeks using an osmotic minipump 72 h after streptozotocin treatment. NADPH-oxidase activity and Nox4 protein expression were increased in diabetic left ventricles (LV) compared to non-diabetic control animals. Treatment with AS but not S decreased NADPH-oxidase activity and prevented the increase in Nox4 expression in LV homogenates. ROS generation measured by DHE staining was increased in the LV of diabetic animals and was prevented in the AS but not sense-treated animals. Moreover, the increased expression of fibronectin, α-smooth muscle actin and β-myosin heavy chain protein in the LV of diabetic rats was markedly reduced in AS but not sense-treated diabetic rats. Echocardiographic measurements show that depressed LV systolic function (ejection fraction and shortening fraction) in diabetic rats was prevented in AS but not sense-treated animals. Exposure of cultured cardiac myocytes to 25mM glucose resulted in increased NADPH-oxidase activity, Nox4 protein expression and in myocytes hypertrophy. These effects of high glucose were prevented in cells infected with dominant negative Nox4 adenovirus. These data establish a role for Nox4 as an important source of ROS in the LV during early stages of diabetes and establish that Nox4-derived ROS mediate cardiomyopathy phenotype in diabetes.