MiRNA‐181a is a novel regulator of aldosterone–mineralocorticoid receptor‐mediated cardiac remodelling

Aim The aldosterone–mineralocorticoid receptor (Aldo–MR) pathway is activated during cardiac stress, such as hypertension, myocardial infarction (MI), and heart failure. The importance of Aldo and MR in the pathogenesis of cardiac diseases is well established; however, the regulatory mechanisms behind Aldo/MR‐induced cardiac remodelling remain uncertain. We here investigated potential miRNA‐mediated regulation of the Aldo–MR pathway to improve mechanistic understanding. Methods and results High‐throughput screening of 2,555 miRNAs using an MR responsive stable cardiomyocyte cell line (MMTV‐GFP‐HL‐1) identified miR‐181a as a potential regulator of Aldo–MR pathway. MiR‐181a was found to downregulate the expression of Ngal (lipocalin‐2), a well‐established downstream effector molecule of Aldo–MR. In addition, Aldo‐induced cellular hypertrophy decreased significantly upon miR‐181a overexpression. Genetic miR‐181 knockout in murine MI model led to deteriorated cardiac function, cardiac remodelling, and activation of Aldo–MR pathway while AAV9‐mediated miR‐181a overexpression improved cardiac function and deactivated Aldo–MR pathway proving a cardio‐protective role of miR‐181a. Global RNA sequencing of cells under Aldo treatment with/without miR‐181a overexpression identified potential miR‐181a targets functionally contributing to Aldo–MR pathway. Adamts1, a direct target of miR‐181a, was found to be downregulated with miR‐181a overexpression and upregulated with inhibition. Similar to miR‐181a overexpression, siRNA‐mediated inhibition of Adamts1 inhibited Aldo–MR pathway. Conclusion We here show that miR‐181a is a novel regulator of the Aldo–MR pathway regulating the levels of Ngal via direct targeting of Adamts1. This new insight establishes miR‐181a as a factor of immense value participating in downstream networks of Aldo–MR pathway. Our in vivo studies further confirmed miR‐181a as cardio‐protective under MI stress. Thus, miR‐181a's involvement in Aldo–MR‐mediated cardiac remodelling confers it with tremendous potential to be developed further as a new therapeutic target.