Carvedilol-responsive microRNAs, miR-199a-3p and -214 protect cardiomyocytes from simulated ischemia-reperfusion injury

Abstract

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.

G Protein–Coupled Receptor Signaling Through β-Arrestin–Dependent Mechanisms

“…185–190 miR-199a-3p and miR-214 are activated by carvedilol in cardiomyocytes subjected to ischemia/reperfusion and promote cardiomyocyte survival by activating p-Akt survival signaling, inducing the expression SRY (sex determining region Y)-box 2 (Sox2), a transcription factor that promotes pluripotency and also by repressing the apoptosis-associated genes ddit4 (DNA damage-inducible transcript 4) and ing4 (inhibitor of growth family member 4). 191 miR-190 upregulation by carvedilol occurs via the β 1 AR and is independent of β 2 AR and α 1 AR activation. It also requires specific activated conformations of the receptor, β 1 AR’s phosphorylation by GRKs 5 or 6 and the recruitment of β-arrestin1 to the carvedilol bound-receptor complex.…”

Overexpression of miR‐199/214 is a distinctive feature of iron‐induced and asbestos‐induced sarcomatoid mesothelioma in rats

“…The miR‐214‐deficient mice were susceptible to lethal ischemia‐reperfusion (I/R)‐induced myocardial oxidative injury with increased Ca 2+ overload and pro–apoptotic Bcl2l11, 46 while overexpression of miR‐214 protected the heart from I/R injury through suppression of PTEN, Bcl2l11, 47 ddit4 or ing4 48 . In contrast, the inhibition of miR‐199 or miR‐214 suppressed cellular proliferation in primary pancreatic stellate cells, 49 suggesting a potential therapeutic target in pancreatic cancer.…”

MiRNA Expression Profile of the Myocardial Tissue of Pigs with Coronary Microembolization

“…However, since this disease is associated with multiple factors, new regulatory factors that are of significant importance need to be identified. Studies in recent years have found that miRNAs, as a post-transcriptional regulatory factor, can simultaneously target multiple mRNAs involved in different signaling pathways, and thereby regulate gene expression either at the transcriptional or at the post-transcriptional level [28]. Thus, various intracellular cytokines and signaling pathways work in synergy under miRNA regulation [29].…”