Smad3 Inactivation and MiR-29b Upregulation Mediate the Effect of Carvedilol on Attenuating the Acute Myocardium Infarction-Induced Myocardial Fibrosis in Rat

Abstract

Carvedilol, a nonselective β-adrenoreceptor antagonist, protects against myocardial injury induced by acute myocardium infarction (AMI). The mechanisms underlying the anti-fibrotic effects of carvedilol are unknown. Recent studies have revealed the critical role of microRNAs (miRNAs) in a variety of cardiovascular diseases. This study investigated whether miR-29b is involved in the cardioprotective effect of carvedilol against AMI-induced myocardial fibrosis. Male SD rats were randomized into several groups: the sham surgery control, left anterior descending (LAD) surgery-AMI model, AMI plus low-dose carvedilol treatment (1 mg/kg per day, CAR-L), AMI plus medium-dose carvedilol treatment (5 mg/kg per day, CAR-M) and AMI plus high-dose carvedilol treatment (10 mg/kg per day, CAR-H). Cardiac remodeling and impaired heart function were observed 4 weeks after LAD surgery treatment; the observed cardiac remodeling, decreased ejection fraction, and fractional shortening were rescued in the CAR-M and CAR-H groups. The upregulated expression of Col1a1, Col3a1, and α-SMA mRNA was significantly reduced in the CAR-M and CAR-H groups. Moreover, the downregulated miR-29b was elevated in the CAR-M and CAR-H groups. The in vitro study showed that Col1a1, Col3a1, and α-SMA were downregulated and miR-29b was upregulated by carvedilol in a dose-dependent manner in rat cardiac fibroblasts. Inhibition of ROS-induced Smad3 activation by carvedilol resulted in downregulation of Col1a1, Col3a1, and α-SMA and upregulation of miR-29b derived from the miR-29b-2 precursor. Enforced expression of miR-29b significantly suppressed Col1a1, Col3a1, and α-SMA expression. Taken together, we found that smad3 inactivation and miR-29b upregulation contributed to the cardioprotective activity of carvedilol against AMI-induced myocardial fibrosis.

Role of the microRNA-29 family in fibrotic skin diseases

“…The authors determined that carvedilol treatment exerts its effect via inhibition of Smad3 signalling and activation of miR-29b expression. Forced overexpression by miRNA mimics also exerted similar effects, which was demonstrated by a significant decrease in Col1A1, Col3α1, and α-smooth muscle actin expression levels in the two experimental conditions (71). In another example, van Rooij et al (41) suggested that restoring miRNA expression with synthetic oligonucleotides (miRNA mimics) or pharmacological inhibitors may be a useful approach to counteract the adverse effects of miR-29 downregulation in myocardial fibrosis.…”

“…In one example, Zhu et al (71) indicated that carvedilol, a non-selective β-adrenoreceptor antagonist, attenuates myocardial fibrosis in rats. The authors determined that carvedilol treatment exerts its effect via inhibition of Smad3 signalling and activation of miR-29b expression.…”

miRNome in myocardial infarction: Future directions and perspective

“…COL1A1, COL3A1, and α-SMA were downregulated and miR-29b was upregulated by carvedilol in a dose-dependent manner in rat CFs. Enforced expression of miR-29b significantly suppressed COL1A1, COL3A1, and α-SMA expression [52] . An alternative strategy has also been hypothesized that overexpression of miR-29b, which would inhibit mRNAs that encode CF proteins involved in fibrosis, would similarly facilitate progenitor cell migration into the infarcted rat myocardium.…”

Carvedilol and Cardiac Biomarkers in Dialysis Patients: Secondary Analysis of a Randomized Controlled Trial

“…Furthermore, one uncontrolled [13] and one randomized controlled trial [14] have demonstrated a reduction in BNP in patients receiving dialysis treated with BBA, raising the possibility that these agents reduce myocardial stretch. Galectin-3 is a marker of cardiac fibrosis, a process that may be reduced by the antioxidant properties of carvedilol [15], and has been associated with adverse outcomes in ESKD [16, 17]. However, galectin-3 may be elevated with fibrosis in other organs.…”