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- Title
Cardiac Overexpression of Hormone-Sensitive Lipase Inhibits Myocardial Steatosis in Diabetic Mice.
- Authors
Ueno, Masami; Suzuki, Jinya; Kasen, Miki; Zenimaru, Yasuo; Takahashi, Sadao; Koizumi, Tsutomu; Kraemer, Fredric B.; Miyamori, Isamu
- Abstract
Intracellular accumulation of triglyceride (TG) is a key feature of diabetic cardiomyopathy. The excess release of fatty acids from TG droplets has been shown to cause lipotoxicity for cardiomyocytes. Cardiac intracellular lipolysis is regulated by lipases including hormone-sensitive lipase (HSL). We have identified that cardiac HSL is activated in diabetes, although its pathophysiological function remains unclear. To explore the effect of HSL-activation on diabetic cardiomyopathy, we have generated transgenic mice with heart-specific overexpression of HSL and studied the cardiac phenotype in diabetic condition. The heart-specific HSL overexpressing mice were created using a transgene containing rat HSL cDNA under a myosin heavy chain-cα promoter. The founders were backcrossed with C57BL/6 mice for 6 generations and the heterozygous transgenic (Tg) mice were studied. Diabetes was induced by i.p. injection of streptozotocin and cardiac lipid and histological analysis were performed. Cardiac gene expressions were analyzed by quantitative RT-PCR. In the heart of diabetic C57BL/6 mice, both mRNA and protein expression of HSL were increased 2-fold, and HSL activity was elevated 75% 3 wks after the induction of diabetes compared with non-diabetic mice. Cardiac TG content was increased 2-fold and lipid droplet accumulation was observed by oil-red O staining in the diabetic mice. Tg mice showed robust protein expression of HSL and 8-fold higher HSL activity in a heart-specific manner. By electron microscopy, Tg mice showed almost no lipid droplets in cardiomyocytes in contrast to wildtype (Wt) hearts where many lipid droplets clustered around mitochondria. Cardiac TG content was 2-times lower in Tg mice compared to Wt mice in both diabetic and non-diabetic conditions. The mRNA expression of the rate-limiting enzymes for TG synthesis, phosphatidate phosphatase 2A and 2B, were 40% upregulated in diabetic Wt hearts, but these increases were blunted in Tg hearts. The expression of matrix metalloproteinase 2 was 50% lower in Tg hearts compared to Wt hearts in both diabetic and non-diabetic conditions, and the expression of typeXV collagen was 80% lower in diabetic Tg hearts compared to Wt hearts. The results show that cardiac overexpression of HSL inhibits diabetes-induced cardiac steatosis, and alters gene expressions for TG synthesis and collagen metabolism. Thus, cardiac HSL could be a target to regulate diabetic cardiomyopathy.
- Subjects
TRIGLYCERIDES; CARDIOMYOPATHIES; HEART cells; FATTY acids; DIABETES; GENE expression; LABORATORY mice
- Publication
Diabetes, 2007, Vol 56, pA14
- ISSN
0012-1797
- Publication type
Article