Endothelial Cell-Derived Endothelin-1 Promotes Cardiac Lipid Accumulation in Diabetic Heart

Bambang Widyantoro1,2, Noriaki Emoto1, Takashi Suzuki4, Masashi Yanagisawa3, Ken-ichi Hirata1. 1Kobe University Graduate School of Medicine, Division of Cardiovascular Medicine, Japan, 2Faculty of Medicine University of Indonesia, Department of Cardiology and Vascular Medicine, Indonesia, 3University of Texas Southwestern Medical Center, Howard Hughes Institute, United States, 4Tohoku University Graduate School of Medicine, Department of Pathology, Japan.

Persistently high plasma endothelin-1 (ET-1) in diabetes patients has been associated with development of diabetic cardiomyopathy, of which cardiac lipotoxicity being proposed as central in the pathophysiology. Recently we reported that ET-1 contributes to development of cardiac fibrosis in late stage of diabetic heart. Here we hypothesize that ET-1 might contribute to lipid accumulation and oxidative stress in early stage of diabetic heart. To test this hypothesis, we developed type 1 diabetes model by streptozotocin injection in vascular endothelial cell-specific ET-1 knockout (VEETKO) mice, of which ET-1 expression in the heart were reduced by 60%, and to its wild type (WT) littermates. Diabetes increased cardiac ET-1 expression in WT heart 1.5 folds of that in VEETKO heart, which revealed stimulation of ET-1 production from endothelial cells. Electron microscopy shows disruption of cardiac mitochondria and myofibrils, along with accumulation of lipid droplets in WT heart after 8 weeks of hyperglycemia, but not in VEETKO heart. Cardiac content of triacylglycerol and nonesterified fatty acids were increased in WT heart, which were prevented in VEETKO mice (21.13±4.08 vs.14.95±6.3 mg/g heart, p<0.01, n = 5 each). This lipid accumulation further stimulates higher superoxide production in WT heart as compared to VEETKO heart, as shown by lucigenin chemoluminescence assay (6.2±0.8 vs. 2.6±0.5 CPM/g dried heart, p<0.01, respectively). Interestingly, we observed similar cardiac apoptosis rate in both genotypes which suggest possible anti-apoptotic properties of ET-1 in cardiomyocyte. However, prominent cardiac lipotoxicity and oxidative stress in WT heart further leads to progression of cardiac dysfunction in WT mice. In conclusion, our study shows that endothelial cells-derived ET-1 involved in lipid accumulation and superoxide production in early stage of diabetes heart. The precise mechanism linking ET-1 with cardiac lipid accumulation remains to be investigated.