Regulation of cardiac miR-208a, an inducer of obesity, by Rapamycin and Nebivolol

OBJECTIVE: Resistance to obesity is observed in rodents and humans treated with Rapamycin (Rap) or Nebivolol (Neb). Since cardiac miR-208a promotes obesity, we tested whether the modes of actions of Rap and Neb involve inhibition of miR-208a. METHODS: Mouse cardiomyocyte HL-1 cells and Zucker obese (ZO) rats were used to investigate regulation of cardiac miR-208a. RESULTS: Angiotensin II (Ang II) increased miR-208a expression in HL-1 cells. Pre-treatment with an AT1 receptor (AT1R) antagonist, losartan (1µM), antagonized this effect, whereas a phospholipase C inhibitor, U73122 (10µM) and an NADPH oxidase inhibitor, apocynin (0.5mM) did not. Ang II-induced increase in miR-208a was suppressed by Rap (10nM), an inhibitor of nutrient sensor kinase mTORC1, and Neb (1µM), a 3(rd) generation β-blocker that suppressed bioavailable AT1R binding of (125)I-Ang II. Thus, suppression of AT1R expression by Neb, inhibition of AT1R activation by losartan, and inhibition of AT1R-induced activation of mTORC1 by Rap attenuated the Ang II-induced increase in miR-208a. In ZO rats, Rap treatment (750µg/kg/day; 12 weeks) reduced obesity despite similar food intake, suppressed cardiac miR-208a, and increased cardiac MED13, a suppresser of obesity. CONCLUSION: Rap and Neb suppress cardiac miR-208a. MiR-208a suppression and increase in MED13 correlated with attenuated weight gain despite leptin resistance.