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  • Ample evidence has shown that ET system plays a


    Ample evidence has shown that ET-1 system plays a pivotal role in the development of cardiovascular anomalies and pharmacological inhibition of ETA prevents the development of cardiac hypertrophy [[37], [38], [39]]. Yanagisawa and coworkers, who first reported the cardiomyocyte-specific endothelin A receptor knockout mice, failed to note any protective effect of ETAKO on angiotensin II or isoproterenol induced cardiac hypertrophic or contractile response [23]. Evidence from our group using the same murine model revealed beneficial effect of ETAKO against aging and cold stress-induced cardiac pathological changes [20, 21]. One plausible reason for this discrepancy may be the compensatory upregulation of ETB receptor [23]. It is also likely that angiotensin II and isoproterenol may be mediating their hypertrophic effects in an endothelin-independent manner. However, our study did not favor compensatory upregulation of ETB receptor in the face of high-fat diet intake. ET-1 and isoproterenol were shown to induce cardiac hypertrophy through distinct signaling mechanisms [40]. While ET-1 phosphorylates glycogen synthase kinase-3β (GSK3β) through the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)/Akt cascades, isoproterenol activates GSK3β primarily via PI3K/Akt signaling. Although the precise mechanisms involved in obesity-associated cardiac hypertrophy and contractile dysfunction remain elusive, it is likely that certain pathways other than neurohormonal signaling may be involved in the observed beneficial effects of ETAKO. Sustained obesity leads to dyslipidemia, DPNI-caged-GABA intolerance, insulin resistance, leptin resistance and inflammation, all of which may predispose devastating cardiac complications such as cardiac hypertrophy and heart failure [[1], [2], [3], 41]. This is supported by elevated cardiac triglycerides, downregulated Ob-R, and compromised insulin signaling (OGTT, phosphorylation of Akt and IRS1, as well as upregulated PTP1B) observed in our study. Although one may argue that high-fat diet per se may predispose cardiac remodeling and contractile dysfunction, findings from our group previously suggested that it is the diet-induced obesity rather than high fat diet itself that promotes cardiac remodeling and contractile dysfunction [42]. At the cellular level, development of cardiac hypertrophy in diet-induced obesity (heart weight, LV mass, and cross-sectional area) involves signaling pathways leading to alterations in gene transcription and protein synthesis such as β-MHC, ANF, GATA4 and NFATc3 as observed in our current study. Calcineurin-mediated dephosphorylation of NFATc leads to its nuclear translocation to interact with cardiac–restricted zinc finger protein GATA-4, en route to the upregulation of hypertrophic genes [43]. In this study, we found that ETAKO attenuated high-fat diet-mediated upregulation of hypertrophic genes and proteins, consistent with its response on cardiac hypertrophy. Ehmke and co-workers found similar rises in hypertrophic proteins associated with renal artery clipping in mice, the effect of which was inhibited by a pharmacological ETA receptor antagonist [44]. These authors did not observe any changes in blood pressure following ETA receptor blockade, suggesting a cardiomyocyte-specific effect. This is also consistent with our observations, where ETAKO failed to alter global parameters such as body (and liver/kidney) weight, blood pressure and glucose handling. Furthermore, our in vitro finding that exogenous palmitic acid challenge triggered upregulation of pro-hypertrophic proteins in cardiomyocytes, which was abolished by the ETA receptor blocker BQ123. In conjunction with the elevated ETA receptor levels in fat diet-induced obesity, our findings have substantiated the notion of ET-1 in the onset and development of cardiac hypertrophy in obesity. It is noteworthy that leptin signaling and PTP1B were unlikely involved in ETAKO-elicited beneficial cardiac geometric and functional responses.