Inhibition of protein kinase β2 attenuates NOS uncoupling and myocardial dysfunction in streptozotocin-induced diabetic rats

Abstract

Hyperglycemia induced protein kinase C (PKC) β activation is implicated in diabetic cardiomyopathy, which is also associated with impaired function of endothelial nitric oxide (NO) synthase (eNOS). We postulated that PKCβ2 inhibition may attenuate myocardial dysfunction by rescuing eNOS function and reducing eNOS uncoupling in streptozotocin (STZ)-induced diabetes. Control (C) or STZ-induced diabetic (D) rats were treated or untreated with PKCβ inhibitor LY333531 (LY, 1 mg/kg/day) for four weeks. The ratio of peak velocity of early and late diastolic filling (E/A) measured by echocardiography was decreased, while left ventricular isovolumic relaxation time (IVRT) and the heart to body weight ratio were increased in D rats. All of these changes were attenuated by LY (P<0.05 D vs. C). Cardiac O2− and nitrotyrosine production were increased, whereas NO were decreased in D rats. Diabetes induced increase of O2− levels was blocked by the NOS inhibitor L-NAME, indicating “NOS uncoupling”. In addition, cardiac iNOS expression was increased, while levels of eNOS, p-eNOS (Ser 1177) and p-Akt (Ser 473) expression were decreased in D rats. All the alterations were attenuated or reversed by LY. We conclude that PKCβ2 inhibition may attenuate myocardrial dysfunction in diabetes by restoring Akt-dependent eNOS/NO signaling and maintaining eNOS coupling.

Supported by RGC/GRF (782910, 766709)