Original investigation

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

Olga Bilim¹ , Yasuchika Takeishi¹ , Tatsuro Kitahara¹ , Takanori Arimoto¹ , Takeshi Niizeki¹ , Toshiki Sasaki¹ , Kaoru Goto² and Isao Kubota¹

¹  Department of Cardiology, Pulmonology and Nephrology, Yamagata University School of Medicine, Yamagata, Japan

²  Department of Anatomy and Cell Biology, Yamagata University School of Medicine, Yamagata, Japan

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Cardiovascular Diabetology 2008, 7:2doi:10.1186/1475-2840-7-2

Published:	4 February 2008

Abstract

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 PKCβ attenuates insulin-stimulated Akt phosphorylation.

Methods and Results

We examined transgenic mice with cardiac-specific overexpression of DGKζ (DGKζ-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 DGKζ-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 DGKζ-TG mice. Thinning of the interventricular septum and the posterior wall in diabetic WT hearts were blocked in DGKζ-TG mice. Reduction of transverse diameter of cardiomyocytes isolated from the left ventricle in diabetic WT mice was attenuated in DGKζ-TG mice. Cardiac fibrosis was much less in diabetic DGKζ-TG than in diabetic WT mice. Western blots showed translocation of PKCβ and δ isoforms to membrane fraction and decreased Akt/PKB phosphorylation in diabetic WT mouse hearts. However in diabetic DGKζ-TG mice, neither translocation of PKC nor changes Akt/PKB phosphorylation was observed.

Conclusion

DGKζ modulates intracellular signaling and improves the course of diabetic cardiomyopathy. These data may suggest that DGKζ is a new therapeutic target to prevent or reverse diabetic cardiomyopathy.