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.


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.


CONCLUSIONS
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.
Bilim
Olga
O
Department of Cardiology, Pulmonology and Nephrology, Yamagata University School of Medicine, Yamagata, Japan. obilim@med.id.yamagata-u.ac.jp
Takeishi
Yasuchika
Y
Kitahara
Tatsuro
T
Arimoto
Takanori
T
Niizeki
Takeshi
T
Sasaki
Toshiki
T
Goto
Kaoru
K
Kubota
Isao
I
D000818:Animals; D001284:Atrophy; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000000981:diagnostic imaging / Q000473:pathology / Q000517:prevention & control*; D019852:Diacylglycerol Kinase / Q000235:genetics / Q000378:metabolism*; D004452:Echocardiography; D006321:Heart / Q000033:anatomy & histology / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology; D009929:Organ Size; D013311:Streptozocin; D018487:Ventricular Dysfunction, Left / Q000201:enzymology / Q000473:pathology
D013311:Streptozocin; D019852:Diacylglycerol Kinase; C512480:diacylglycerol kinase zeta, mouse