In the modern society, obesity has become the major risk factor of heart diseases. Endothelin-1 (ET-1), which plays an important role in regulating cardiovascular functions, mediates its effects on cardiovascular system through its receptors, endothelin receptor-1A (ETA), that are abundant in the heart. To investigate the role of ETA on obesity-induced cardiac dysfunction, we randomly assigned Endothelin-1 receptor A knockout (ETAKO) mice and wild-type C57BL/6 mice to receive either high-(45%

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... t) (HF) or low-(10% fat) (LF) fat diets starting from their 5-6 weeks of age for 24 weeks. HF-diet enhanced body weight, heart weight and size, and impaired glucose tolerance in C57BL/6. Although ETAKO did not have altered glucose tolerance, it was associated with a reduction in body weight, heart weight and size. Echocardiography revealed that increased left ventricular mass and wall thickness in C57BL/6 HF-fed mice, which were mitigated by ETAKO. HF-diet compromised myocardial contractile function and intracellular Ca2+ handling, which were significantly attenuated by ETAKO. Western blot demonstrated that HF-diet increased the levels of hypertrophy-related proteins and reduced the levels of autophagy-related proteins whereas contrasting results were seen with EKTO-ETAKO reduced the hypertrophy-related protein expressions while increasing autophagy-related protein expressions. Our results suggest ETAKO may rescue the heart from obesity-associated cardiac dysfunction.