Carvedilol-responsive microRNAs, miR-199a-3p and -214 protect cardiomyocytes from simulated ischemia-reperfusion injury.
The nonselective β-adrenergic receptor antagonist (β-blocker) carvedilol has been shown to protect against myocardial injury, but the detailed underlying mechanisms are unclear. We recently reported that carvedilol stimulates the processing of microRNA (miR)-199a-3p and miR-214 in the heart via β-arrestin1-biased β1-adrenergic receptor (β1AR) cardioprotective signaling. Here, we investigate whether these β-arrestin1/β1AR-responsive miRs mediate the beneficial effects of carvedilol against simulated ischemia/reperfusion (sI/R). Using cultured cardiomyocyte cell lines and primary cardiomyocytes, we demonstrate that carvedilol upregulates miR-199a-3p and miR-214 in both ventricular and atrial cardiomyocytes subjected to sI/R. Overexpression of the two miRs in cardiomyocytes mimics the effects of carvedilol to activate p-AKT survival signaling and the expression of a downstream pluripotency marker Sox2 in response to sI/R. Moreover, carvedilol-mediated p-AKT activation is abolished by knockdown of either miR-199a-3p or miR-214. Along with previous studies to directly link the cardioprotective actions of carvedilol to upregulation of p-AKT/stem cell markers, our findings suggest that the protective roles of carvedilol during ischemic injury are in part attributed to activation of these two protective miRs. Loss of function of miR-199a-3p and miR-214 also increases cardiomyocyte apoptosis after sI/R. Mechanistically, we demonstrate that miR-199a-3p and miR-214 repress the predictive or known apoptotic target genes ddit4 and ing4, respectively, in cardiomyocytes. These findings suggest pivotal roles for miR-199a-3p and miR-214 as regulators of cardiomyocyte survival and contributors to the functional benefits of carvedilol therapy.
Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia;
Kyoung-Mi
KM
Park
Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia;
Jian-Peng
JP
Teoh
Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia;
Yongchao
Y
Wang
Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia;
Zuzana
Z
Broskova
Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia;
Ahmed S
AS
Bayoumi
Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia; Department of Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia;
Yaoliang
Y
Tang
Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia; Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia;
Huabo
H
Su
Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia; Department of Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia;
Neal L
NL
Weintraub
Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, Georgia ilkim@augusta.edu.
Il-Man
IM
Kim
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002460:Cell Line; D002478:Cells, Cultured; D003198:Computer Simulation; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000187:drug effects* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015427:Reperfusion Injury / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; C552425:MIRN199 microRNA, rat; D035683:MicroRNAs; C534780:Mirn199 microRNA, mouse; C534781:Mirn214 microRNA, mouse; C559947:Mirn214 microRNA, rat; D011412:Propanolamines; D000077261:Carvedilol
apoptosis; heart disease; microRNAs; β-arrestin-biased β-adrenergic receptor signaling; β-blocker