Modulation of microRNA miR‐29c in a novel cross‐talk between mTOR complex 1 and Angiotensin II type 2 receptor AT2R: an adaptive mechanism in over‐nutrition

Abstract

The microRNA miR‐29c that inhibits INSIG‐1 and insulin (INS) metabolic signaling is up‐regulated in tissues from diabetic animals and plasma of diabetic patients. Our analysis by MiRecords identified a novel target for miR‐29, the Angiotensin II type 2 receptor AT2R. Since AT2R is cardio‐protective, we posited that conditions that activate mTORC1 in cardiac tissue can down‐regulate miR‐29c and thus up‐regulate AT2R. In HL‐1 cardiomyocytes exposed to INS (100nM), mTORC1 was activated as evidenced by phosphorylation (p) of S6K1 (pThr389) and 4E‐BP (pThr37/Thr46), miR‐29c was down‐regulated, and AT2R protein, but not mRNA, was up‐regulated (p < 0.05). mTORC1 inhibitors Rapamycin (Rap: 10nM) and Dexamethasone (Dexa:5μM) ablated mTORC1, up‐regulated miR‐29c and disrupted mTOR→miR‐29→AT2R pathway (p < 0.05). Conversely, a novel AT2R agonist Novokinin (Nov: 1μM) normalized excess mTORC1 activation, but also reduced miR‐29c (p < 0.05) in HL‐1 cells and in cardiac tissues of Zucker obese (ZO rats: 12‐week) subjected to a 9‐day Nov infusion (200μg•kg−1•day−1). Further, Nov improved myocardial performance index in ZO rats. Thus, commonly used mTORC1 inhibitors Rap and Dexa up‐regulate miR‐29 and exacerbate inhibition of INS metabolic signaling whereas AT2R agonist Nov attenuates excess mTORC1 without inducing miR‐29 up‐regulation and subsequent exacerbation of insulin resistance.