br Conclusions br Declaration of interest
Declaration of interest
Introduction Uncorrected obesity has been a major health problem and the prevalence of obesity is fast rising reaching an epidemic proportion [, , ]. Ample of clinical and experimental evidence has suggested that obesity leads to intrinsic changes in the heart including cardiac hypertrophy, an adaptive response initially capable of compensating for the increased myocardial workload, in an effort to maintain normal cardiac function. However, with persistent fat diet intake and adiposity, the physiological cardiac remodeling often develops into maladaptive pathological hypertrophy, resulting in progression of cardiac contractile dysfunction and ultimately heart failure [, , ]. Not surprisingly, obesity is deemed as a major independent risk factor for the ever-rising cardiac morbidity and mortality [, , ]. Endothelin-1 (ET-1) is a potent vasoconstrictor peptide released in vascular endothelium and participates in a wide variety of pathophysiological processes . Aberrant production and activity of ET-1 are considered a hallmark of obesity and related cardiovascular dysfunction [10, 11]. ET-1 exerts its biological effects via the ETA and ETB receptors. Although both receptors are ubiquitously expressed, >90% of ET receptors in cardiomyocytes are ETA subtype . Human and animal studies have indicated elevated plasma and tissue levels of ET-1, and enhanced NE 100 hydrochloride mg of ETA receptors in various cardiovascular anomalies [, , , ]. Consequently, ET-1 receptor antagonists have displayed beneficial therapeutic effects against ischemia-reperfusion injury, aging, cold stress, endothelial dysfunction, hypertension, cardiovascular remodeling, and heart failure [, , , , ]. However, little information is available for the role of ET-1 inhibition in obesity-associated cardiac dysfunction. Given the essential role for ET-1 in the pathogenesis and therapeutics in cardiovascular disease in particular obesity complications [10, 11, , , ], this study was designed to evaluate the impact of knockout of ETA (ETAKO) on cardiac function in a high-fat diet-induced model of obesity. In an effort to examine the possible mechanism of action involved in ETAKO-offered response against obesity cardiomyopathy, if any, wild-type (WT) and cardiac-specific ETA knockout mice were fed high-fat or low-fat diet for 6 months prior to the assessment of cardiac geometry, morphology, insulin sensitivity, apoptosis, energy sensing, substrate utilization, and the mitochondrial biogenesis cofactor peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α).
Materials and methods
Discussion Aberrant production and activity of ET-1 are considered hallmarks in obesity [10, 11]. Ample of evidence has documented a detrimental pathological role of ET-1 in the development of heart diseases [, , ]. Consequently, inhibition of ETA may serve as a potential strategy in the management of cardiovascular and metabolic diseases. The salient findings from our current study revealed that cardiomyocyte-specific knockout of ETA receptors attenuated high-fat diet-induced cardiac remodeling, contractile dysfunction, apoptosis, and autophagy failure. These fat diet-induced obesity-associated alterations in cardiac geometry and contractile function were accompanied with elevated cardiac triglycerides, upregulation of hypertrophic genes/proteins (β-MHC, ANF, GATA4 and NFATc3), compromised insulin signaling, activation of the mTOR-signaling and downregulation of autophagy, which were reconciled by ETAKO. Consistent with these in vivo data, in vitro challenge of palmitic acid to mimic obesogenic environment yielded reminiscent changes in pro-hypertrophic and autophagic signaling in murine cardiomyocytes. Interestingly, inhibition of ETA receptor using a pharmacological inhibitor or induction of autophagy (inhibition of mTOR) using rapamycin effectively reversed palmitic acid-induced changes in the aforementioned cellular signaling. Taken together, these results favor the notion that ablation of ETA mitigates high-fat diet-induced deleterious effects on cardiac hypertrophy and contractile dysfunction via down-regulation of mTOR and stimulation of autophagy.