Faculty Articles

Title

Regulation of cardiac miR-208a, an inducer of obesity, by rapamycin and nebivolol

Publication Title

Obesity (Silver Spring)

Volume

23

Issue

11

Publication Date / Copyright Date

11-1-2015

First Page

2251

Last Page

2259

Publisher

Wiley

DOI Number

10.1002/oby.21227

Abstract

OBJECTIVE: Resistance to obesity is observed in rodents and humans treated with rapamycin (Rap) or nebivolol (Neb). Because cardiac miR-208a promotes obesity, this study 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. Pretreatment with an AT1 receptor (AT1R) antagonist, losartan (1 μM), antagonized this effect, whereas a phospholipase C inhibitor, U73122 (10 μM), and an NADPH oxidase inhibitor, apocynin (0.5 mM), did not. Ang II-induced increase in miR-208a was suppressed by Rap (10 nM), an inhibitor of nutrient sensor kinase mTORC1, and Neb (1 μM), a 3rd 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 (750 μg kg(-1) day(-1) ; 12 weeks) reduced obesity despite similar food intake, suppressed cardiac miR-208a, and increased cardiac MED13, a suppresser of obesity.

CONCLUSIONS: Rap and Neb suppressed cardiac miR-208a. Suppression of miR-208a and increase in MED13 correlated with attenuated weight gain despite leptin resistance.

Disciplines

Medicine and Health Sciences | Pharmacy and Pharmaceutical Sciences

Keywords

Angiotensin II, Animals, Cells, Cultured, Gene Expression Regulation, Male, Mediator Complex, Mice, MicroRNAs, Myocytes, Cardiac, Nebivolol, Obesity, Rats, Rats, Zucker, Signal Transduction, Sirolimus, Weight Gain

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