β-arrestin-biased agonism of β-adrenergic receptor regulates Dicer-mediated microRNA maturation to promote cardioprotective signaling

Abstract

Our findings indicate a novel role for βAR-mediated β-arrestin signaling activated by carvedilol in Dicer-mediated miR maturation, which may be linked to its protective mechanisms.

MicroRNA‑1 downregulation induced by carvedilol protects cardiomyocytes against apoptosis by targeting heat shock protein 60

“…miR-125b-5p protected the heart against acute MI by inhibiting the death of cultured cardiomyocytes in response to injury, partially through the suppression of the pro-apoptotic genes Bcl-2 antagonist/killer 1 and Krüppel like factor 13 (37). Carvedilol-mediated upregulation of miR-466g or miR-532-5p was identified to be dependent on β2-ARs, and upregulation of miR-674 by carvedilol was identified to be dependent on β1-ARs (38). β2-AR/β-arrestin-responsive miR-532 conferred cardioprotection against MI though serving as a gatekeeper of cardiac vascularization by repressing a known endothelial-to-mesenchymal transition initiator, serine protease 23 (39).…”

“…It should be noted that the present study does not provide insight into the mechanism of action of carvedilol and miR-1. Previous studies have suggested that β-AR/β-arrestin signaling is involved in miRNA maturation regulatory network activated by carvedilol, which may be associated with the protective effects of this therapeutic agent (36,38). Therefore, there is an urgent requirement for additional investigations into the effects of gain or loss-of-function of the regulatory mechanism proposed in the present study in the pathophysiology of cardiovascular diseases.…”

Three miRNAs cooperate with host genes involved in human cardiovascular disease

“…miRNAs have been implicated in a wide variety of cardiovascular disorder, including heart failure, cardiac hypertrophy, remodeling after myocardial infarction, arrhythmias, atherosclerosis, atrial fibrillation, and peripheral artery disease [5, 6]. Studies have shown that miRNAs play important roles in cardiac signaling and transcriptional pathways and that they act as “rheostats” and “switches” to modulate various aspects of cardiac development [7, 8]. Deregulated miRNA expression profiles were detected in patients with cardiac vascular disease [9, 10].…”

“…Deregulated miRNA expression profiles were detected in patients with cardiac vascular disease [9, 10]. Functions in cardiac-associated pathways for some miRNAs have been verified, e.g., MiR-18a-5p inhibits endothelial-mesenchymal transition and cardiac fibrosis through the Notch2 pathway [7], and some miRNAs act as gatekeepers of cardiac cell functions by repressing deleterious targets [8]. Despite these advances in recent years, many questions remain regarding the mechanistic basis of miRNA activities, and numerous issues must be addressed toward their roles in cardiovascular disease.…”

Recent Advances in β2-Agonists for Treatment of Chronic Respiratory Diseases and Heart Failure

“…Later, Kim and group members discovered that the β-arrestin-biased β 1 AR signaling activated by carvedilol has a novel function of regulating micro-RNA (miR) biogenesis . They subsequently showed that the β 2 AR can also mediates carvedilol-activated β-arrestin-biased signaling, which causes the upregulation of several cardioprotective miRs . Meanwhile, Benovic and group members synthesized allosteric modulator peptides (pepducins) targeting the cytosolic portion of the β 2 AR, with an aim to produce a β-arrestin-biased signaling on a vacant receptor .…”