Ghrelin, a novel gut hormone, has been shown to exert protective effects on cardiac dysfunction and remodeling. However, the underlying mechanisms of its protective effects remain unclear. Here, we investigated the effects of ghrelin on cardiac hypertrophy and explored the mechanisms involved. Ghrelin (30 μg.kg. day) was systemically administered to rats with cardiac hypertrophy induced by abdominal aortic constriction (AAC) by a mini-osmotic pump the next day after surgery continuously for 4 weeks. The AAC treated rats without ghrelin infusion showed decreased ghrelin content and expression of its receptors in the hearts. Exogenous ghrelin greatly attenuated cardiac hypertrophy as shown by heart weight to tibial length (HW/TL), hemodynamics, echocardiography, histological analyses, and expression of hypertrophic markers induced by AAC. This corresponded with decreased cardiac fibrosis and inflammation in the hearts of AAC rats treated with ghrelin. Moreover, ghrelin significantly increased the myocardial expression of autophagy markers, which was further confirmed in cultured cardiomyocytes. Concurrently, cardiomyocyte apoptosis in vivo and in vitro was ameliorated by ghrelin, which was reversed by inhibition of autophagy. The enhancement of autophagy and inhibition of apoptosis by ghrelin were eliminated on pretreatment with compound C, an AMP-activated protein kinase (AMPK) inhibitor. Furthermore, inhibition of Ca/Calmodulin-dependent protein kinase kinase (CaMKK), an upstream kinase of AMPK, made ghrelin fail to activate AMPK and simultaneously reversed ghrelin's promotion of autophagy. In conclusion, ghrelin could exert its cardioprotective effects on cardiac hypertrophy by promoting autophagy, possibly via CaMKK/AMPK signaling pathway.

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http://dx.doi.org/10.1016/j.peptides.2020.170446DOI Listing

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