title: Regulation of cardiac miR-208a, an inducer of obesity, by rapamycin and nebivolol.
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.
authors.affiliation: Department of Medicine, University of Missouri, Columbia, Missouri, USA.|Research Service, Harry S Truman Memorial Veterans Affairs Hospital, Columbia, Missouri, USA.|Obesity Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Rukhsana
authors.initials: R
authors.lastname: Gul
authors.affiliation: Department of Medicine, University of Missouri, Columbia, Missouri, USA.|Research Service, Harry S Truman Memorial Veterans Affairs Hospital, Columbia, Missouri, USA.
authors.forename: Abuzar
authors.initials: A
authors.lastname: Mahmood
authors.affiliation: Department of Medicine, University of Missouri, Columbia, Missouri, USA.|Research Service, Harry S Truman Memorial Veterans Affairs Hospital, Columbia, Missouri, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Luck
authors.affiliation: Department of Medicine, University of Missouri, Columbia, Missouri, USA.|Research Service, Harry S Truman Memorial Veterans Affairs Hospital, Columbia, Missouri, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Lum-Naihe
authors.affiliation: Obesity Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Assim A
authors.initials: AA
authors.lastname: Alfadda
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University, Washington, DC, USA.|College of Pharmacy, Nova Southeastern University, Fort Lauderdale, Florida, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Speth
authors.affiliation: Department of Medicine, University of Missouri, Columbia, Missouri, USA.|Research Service, Harry S Truman Memorial Veterans Affairs Hospital, Columbia, Missouri, USA.|Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, USA.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Pulakat
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D056892:Mediator Complex / Q000502:physiology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D000068577:Nebivolol / Q000494:pharmacology*; D009765:Obesity / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology*; D015430:Weight Gain / Q000187:drug effects / Q000235:genetics
chemical_list: C569395:MIRN208 microRNA, rat; D056892:Mediator Complex; D035683:MicroRNAs; D000068577:Nebivolol; D000804:Angiotensin II; D020123:Sirolimus