MiR‐133a regulates collagen 1A1: Potential role of miR‐133a in myocardial fibrosis in angiotensin II‐dependent hypertension

Abstract

MicroRNAs play an important role in myocardial diseases. MiR-133a regulates cardiac hypertrophy, while miR-29b is involved in cardiac fibrosis. The aim of this study was to evaluate whether miR-133a and miR-29b play a role in myocardial fibrosis caused by Angiotensin II (Ang II)-dependent hypertension. Sprague-Dawley rats were treated for 4 weeks with Ang II (200 ng/kg/min) or Ang II + irbesartan (50 mg/kg/day in drinking water), or saline by osmotic minipumps. At the end of the experimental period, cardiac miR-133a and miR-29b expression was measured by real-time PCR, and myocardial fibrosis was evaluated by morphometric analysis. A computer-based prediction algorithm led to the identification of collagen 1a1 (Col1A1) as a putative target of miR-133a. A reporter plasmid bearing the 3'-untranslated regions (UTRs) of Col1A1 mRNA was constructed and luciferase assay was performed. MiR-133a suppressed the activity of luciferase when the reporter gene was linked to a 3'-UTR segment of Col1A1 (P < 0.01). Mutation of miR-133a binding sites in the 3'-UTR of Col1A1 mRNA abolished miR-133a-mediated repression of reporter gene activity, showing that Col1A1 is a real target of miR-133a. In vivo, Ang II caused an increase in systolic blood pressure (P < 0.0001, tail cuff) and myocardial fibrosis in presence of a decrease in miR-133a (P < 0.01) and miR-29b (P < 0.01), and an increase in Col1A1 expression (P < 0.01). These effects were abolished by Ang II administration + irbesartan. These data demonstrate a relationship between miR-133a and Col1A1, suggesting that myocardial fibrosis occurring in Ang II-dependent hypertension is regulated by the down-regulation of miR-133a and miR-29b through the modulation of Col1A1 expression.

MicroRNAs mediate the cardioprotective effect of angiotensin-converting enzyme inhibition in acute kidney injury

“…We found a significant increase in cardiac mRNA for the extracellular matrix protein Col1A1 and Fn1 by STNx, which was attenuated by ramipril treatment. Luciferase gene reporter assays performed in previous studies (9,44) have demonstrated TGF-␤ 1 and Col1A1 as direct targets of microRNA-133. Fn 1 is a direct target of microRNA-1 (61).…”

“…Fn 1 is a direct target of microRNA-1 (61). Treatment with an ANG receptor blocker, irbesartan, upregulates microRNA-133, which, in turn, mediates the inhibition of Col1A1 and the attenuation of myocardial fibrosis in a rat model of ANG II-dependent hypertension (9). Our results suggest that increased microRNA-133 and microRNA-1 after ramipril treatment may be the molecular switch responsible for the inhibition of TGF-␤ 1 -Smad signaling, which, in turn, inhibits Col1A1 and Fn1 mRNA expression.…”

“…A study (51) in null mice and a model of pressure-overload induced heart failure has indicated that microRNA-212 and microRNA-132 regulate cardiac hypertrophy. Others have reported that microRNA-1 and microRNA-133 are associated with cardiovascular pathologies (2,3,10,21,42) and regulate genes involved in cardiac fibrosis and apoptosis (9,21).…”

Influence of serum adiponectin level and SNP +45 polymorphism of adiponectin gene on myocardial fibrosis

“…Studies have shown that angiotensin II (the main active substance in the renin-angiotensin system) can stimulate the hypertrophy of the myocardial cells and hyperplasia of the cardiac fibroblasts (Castoldi et al, 2012). However, these results cannot fully explain the mechanism of myocardial fibrosis caused by high BP (Kai et al, 2009).…”

MicroRNAs Are Involved in End-Organ Damage During Hypertension

“…44 Furthermore, miR-21 and -29 also mediate complex signaling in the development of renal fibrosis [45][46][47][48] and thus seem to modulate similar processes in different target organs (Figure). MiR-133a regulates collagen 1A1 expression, 49 and miR-199 also links antiapoptotic Akt signaling with β-adrenergic stimulation. 50 Finally, miR-199a-5p is regulated by signal transducer and activator of transcription 3, thereby linking cardiomyocyte and endothelial cell function.…”