Diacylglycerol kinase zeta inhibits myocardial atrophy and restores cardiac dysfunction in streptozotocin-induced diabetes mellitus

BACKGROUND: Activation of the diacylglycerol (DAG)-protein kinase C (PKC) pathway has been implicated in the pathogenesis of a number of diabetic complications. Diacylglycerol kinase (DGK) converts DAG to phosphatidic acid and acts as an endogenous regulator of PKC activity. Akt/PKB is associated with a downstream insulin signaling, and PKCbeta attenuates insulin-stimulated Akt phosphorylation. METHODS AND RESULTS: We examined transgenic mice with cardiac-specific overexpression of DGKzeta (DGKzeta-TG) compared to wild type (WT) mice in streptozotocin-induced (STZ, 150 mg/kg) diabetic and nondiabetic conditions. After 8 weeks, decreases in heart weight and heart weight/body weight ratio in diabetic WT mice were inhibited in DGKzeta-TG mice. Echocardiography at 8 weeks after STZ-injection demonstrated that decreases in left ventricular end-diastolic diameter and fractional shortening observed in WT mice were attenuated in DGKzeta-TG mice. Thinning of the interventricular septum and the posterior wall in diabetic WT hearts were blocked in DGKzeta-TG mice. Reduction of transverse diameter of cardiomyocytes isolated from the left ventricle in diabetic WT mice was attenuated in DGKzeta-TG mice. Cardiac fibrosis was much less in diabetic DGKzeta-TG than in diabetic WT mice. Western blots showed translocation of PKCbeta and delta isoforms to membrane fraction and decreased Akt/PKB phosphorylation in diabetic WT mouse hearts. However in diabetic DGKzeta-TG mice, neither translocation of PKC nor changes Akt/PKB phosphorylation was observed. CONCLUSION: DGKzeta modulates intracellular signaling and improves the course of diabetic cardiomyopathy. These data may suggest that DGKzeta is a new therapeutic target to prevent or reverse diabetic cardiomyopathy