TITLE

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

AUTHOR(S)
Bilim, Olga; Takeishi, Yasuchika; Kitahara, Tatsuro; Arimoto, Takanori; Niizeki, Takeshi; Sasaki, Toshiki; Goto, Kaoru; Kubota, Isao
PUB. DATE
January 2008
SOURCE
Cardiovascular Diabetology;2008, Vol. 7, p1
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
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 PKC� attenuates insulin-stimulated Akt phosphorylation. Methods and Results: We examined transgenic mice with cardiac-specific overexpression of DGK? (DGK?-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 DGK?-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 DGK?-TG mice. Thinning of the interventricular septum and the posterior wall in diabetic WT hearts were blocked in DGK?-TG mice. Reduction of transverse diameter of cardiomyocytes isolated from the left ventricle in diabetic WT mice was attenuated in DGK?-TG mice. Cardiac fibrosis was much less in diabetic DGK?-TG than in diabetic WT mice. Western blots showed translocation of PKC� and d isoforms to membrane fraction and decreased Akt/PKB phosphorylation in diabetic WT mouse hearts. However in diabetic DGK?-TG mice, neither translocation of PKC nor changes Akt/PKB phosphorylation was observed. Conclusion: DGK? modulates intracellular signaling and improves the course of diabetic cardiomyopathy. These data may suggest that DGK? is a new therapeutic target to prevent or reverse diabetic cardiomyopathy.
ACCESSION #
55716378

 

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