Rosiglitazone induces cardiac protein kinase C beta2 over-expression and increases ventricular mass in type 2 diabetic db/db mice

Abstract

Rosiglitazone (RSG) treatment in type 2 diabetes has been associated with increased incidence and worsening of heart failure, but the mechanism is unknown. It has been shown that protein kinase C (PKC) β2 is over-expressed in failing human hearts (Circulation 1999;99:384-91) and that RSG-induced weight gain is attributable to increased activation of PKCβ in adipose tissue (FASEB J 2006;20:1203-5). Further, left ventricular mass is reported to be a predictor of heart failure (Eur Heart J 2008;29:741-747). We, therefore, hypothesized that RSG may induce PKCβ2 over-expression and increase ventricular mass of the hearts from db/db (D) mice, a mongenic model of obesity and features of type 2 diabetes. Diabetic mice were either untreated (D), treated with RSG (D+RSG) at 26 mg/kg/day or with RSG plus N-acetylcysteine (NAC, 1.4 g/kg/day) (D+RN), for 3 weeks; NAC can inhibit PKCβ via mechanisms independent of its antioxidant property. Both RSG or RSG+NAC reduced body weight (BW) relative to D group. However, RSG increased ventricular mass and heart weight/BW ratio, accompanied by 1.5-fold increase of myocardial PKCβ2 protein expression and activation as well as increased protein kinase B/AKT phosphorylation at serine-473 relative to D (all P<0.05). NAC prevented all these changes. RGS may have increased ventricular mass by inducing PKCβ2 over-expression.