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

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 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.

• Authors: Olga Bilim, Yasuchika Takeishi, Tatsuro Kitahara, Takanori Arimoto, Takeshi Niizeki, Toshiki Sasaki, Kaoru Goto, Isao Kubota
• Journal: Cardiovascular diabetology (Cardiovasc Diabetol) Vol. 7 Pg. 2 (Feb 04 2008) ISSN: 1475-2840 [Electronic] England
• PMID: 18241357 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Streptozocin
• Diacylglycerol Kinase
• diacylglycerol kinase zeta, mouse

Topics

• Animals
• Atrophy
• Body Weight
• Diabetes Mellitus, Experimental (enzymology, pathology, physiopathology)
• Diabetic Angiopathies (diagnostic imaging, pathology, prevention & control)
• Diacylglycerol Kinase (genetics, metabolism)
• Echocardiography
• Heart (anatomy & histology, physiopathology)
• Mice
• Mice, Transgenic
• Myocardium (enzymology)
• Organ Size
• Streptozocin
• Ventricular Dysfunction, Left (enzymology, pathology)