Abstract 13865: Cardiac Specific Deletion of Endothelin-1 Receptor a Rescues the Heart from High-Fat Diet-Induced Cardiac Dysfunction via Regulating Autophagy
Obesity is a major health concren worldwide and is an important risk factor for heart diseases. The objective of this study was to evaluate the role of endothelin-1 receptor A (ETA) in obesity-associated cardiac dysfunctions. Cardiac specific ETA receptor knock-out (ETAKO) mice and their age- and gender-matched controls (C57BL/6J mice) were randomly assigned to receive either high- fat (45% fat) diet (HFD) or low-fat (10% fat) diet (LFD) starting from their 5-6 weeks of age for 24 weeks. After 24 weeks of feeding, oral glucose tolerance test performed to ensure insulin-resistance. Mice were subjected to echocardiography and cardiomyocyte function assessment. Our data revealed that HFD-feeding compromised myocardial contractile function (fractional shortening, cardiomyocyte peak shortening, maximal velocity of shortening/relengthening and duration of relengthening) and intracellular Ca2+ handling, which were significantly attenuated in the ETAKO. Echocardiography revealed increased left ventricular mass and wall thickness in HF-fed mice, which were mitigated by ETAKO. Western blot of the left ventricle tissue demonstrated that ETAKO had lower levels of hypertrophy-related proteins (ANP, GATA-4). In addition, HFD caused a significant reduction in cardiac autophagy-related proteins (Beclin-1, LC3A-II). Interestingly, ETAKO was resistant to this HFD-induced downregulation of autophagy. Taken together, these results suggest that inhibition of ETA receptor pathway protects against HFD-induced cardiac dysfunction. ETAKO may be mediating these beneficial effects by countering the downregulation of cardiac autophagy associated with obesity.
- © 2011 by American Heart Association, Inc.