The impact of microRNA-122 and its target gene Sestrin-2 on the protective effect of ghrelin in angiotensin II-induced cardiomyocyte apoptosis

Abstract

Ghrelin with n-octanoylated serine 3 residue is a peptide hormone with well-known cardioprotective properties. MicroRNA-122 is associated with the pathogenesis of many cardiovascular diseases, including apoptosis and was found highly increased in our previous rat model of post-myocardial infarction heart failure. In this study, we aimed to identify the target gene of microRNA-122 and to evaluate their impacts on the protective effect of acylated ghrelin in angiotensin II-induced apoptosis. The results showed that microRNA-122 was upregulated in the angiotensin II administration group accompanied by increased cell apoptosis, which were both reversed by ghrelin. Furthermore, microRNA-122 mimics upregulated numerous pro-apoptotic genes and increased apoptosis. The luciferase activity assay revealed Sestrin-2 as a direct target of microRNA-122. The expression of Sestrin-2 was downregulated by angiotensin II and upregulated by co-treatment with ghrelin. Inhibition of microRNA-122 and overexpression of Sestrin-2 alleviated apoptosis which was further reduced upon administered of ghrelin. Together, these results indicated that Sestrin-2 expression is inhibited by microRNA-122 and that this inhibition is involved in the protective effect of ghrelin and angiotensin II-induced apoptosis. We also found that microRNA-122 influenced several apoptosis pathways including the caspase cascade reaction and death receptor-mediated pathways. Collectively, our data reveal that microRNA-122 and its target gene Sestrin-2, under the regulation of angiotensin II and ghrelin, are important players in cardiomyocyte apoptosis. We therefore believe that microRNA-122 and Sestrin-2 can be developed as potential therapeutic targets against apoptosis in cardiovascular diseases.