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MiR‐133a regulates collagen 1A1: Potential role of miR‐133a in myocardial fibrosis in angiotensin II‐dependent hypertension
Author(s) -
Castoldi Giovanna,
di Gioia Cira R.T.,
Bombardi Camila,
Catalucci Daniele,
Corradi Barbara,
Gualazzi Maria Giovanna,
Leopizzi Martina,
Mancini Massimiliano,
Zerbini Gianpaolo,
Condorelli Gianluigi,
Stella Andrea
Publication year - 2012
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.22939
Subject(s) - irbesartan , angiotensin ii , cardiac fibrosis , fibrosis , myocardial fibrosis , microrna , reporter gene , untranslated region , luciferase , endocrinology , medicine , in vivo , chemistry , gene expression , messenger rna , blood pressure , biology , gene , transfection , biochemistry , microbiology and biotechnology
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. J. Cell. Physiol. 227: 850–856, 2012. © 2011 Wiley Periodicals, Inc.