Stress-dependent cardiac remodeling occurs in the absence of microRNA-21 in mice
David M. Patrick, … , Eva van Rooij, Eric N. Olson
David M. Patrick, … , Eva van Rooij, Eric N. Olson
Published November 1, 2010; First published October 18, 2010
Citation Information: J Clin Invest. 2010;120(11):3912-3916. https://doi.org/10.1172/JCI43604.
View: Text | PDF
Category: Brief Report

Stress-dependent cardiac remodeling occurs in the absence of microRNA-21 in mice

Abstract

MicroRNAs inhibit mRNA translation or promote mRNA degradation by binding complementary sequences in 3′ untranslated regions of target mRNAs. MicroRNA-21 (miR-21) is upregulated in response to cardiac stress, and its inhibition by a cholesterol-modified antagomir has been reported to prevent cardiac hypertrophy and fibrosis in rodents in response to pressure overload. In contrast, we have shown here that miR-21–null mice are normal and, in response to a variety of cardiac stresses, display cardiac hypertrophy, fibrosis, upregulation of stress-responsive cardiac genes, and loss of cardiac contractility comparable to wild-type littermates. Similarly, inhibition of miR-21 through intravenous delivery of a locked nucleic acid–modified (LNA-modified) antimiR oligonucleotide also failed to block the remodeling response of the heart to stress. We therefore conclude that miR-21 is not essential for pathological cardiac remodeling.

Authors

David M. Patrick, Rusty L. Montgomery, Xiaoxia Qi, Susanna Obad, Sakari Kauppinen, Joseph A. Hill, Eva van Rooij, Eric N. Olson

×

Figure 3

Cardiac stress response after antimiR-21 treatment.

Options: View larger image (or click on image) Download as PowerPoint
Cardiac stress response after antimiR-21 treatment. (A) Trichrome-staine...
(A) Trichrome-stained sections of hearts show that animals treated with both saline and antimiR-21 (Anti-21) display induction of cardiac hypertrophy upon TAC. (B) HW/BW ratios of mice treated as indicated. HW/BW data represent n = 6 for sham conditions and n = 12 for TAC conditions. (C) Northern blot analysis for miR-21 in cardiac tissue of animals treated as indicated. The upshift reflects a heteroduplex between miR-21 and antimiR-21. RNU6B was a loading control. (D) Real-time RT-PCR analysis of miR-21 expression in cardiac tissue after the indicated treatments. Data represent n = 5 for sham conditions and n = 10 for TAC conditions. Scr, scrambled control. (E) Functional analysis of the heart represented by fractional shortening. Data represent n = 6 for sham conditions and n = 12 for TAC conditions. (F) Western blot analysis indicates a stress-induced increase in phospho-Erk for saline- and antimiR-21–treated mice in response to TAC. (G) Western blot analysis shows an increase in Pdcd4 in antimiR-21–treated mice in response to TAC. (H) Trichrome-stained sections of hearts from animals treated as indicated. Animals treated with both LNA scrambled control and antimiR-21 display induction of cardiac hypertrophy upon Ang II infusion. (I) HW/BW ratios of mice treated as indicated. Ratios represent n = 3 for Scr Saline, n = 4 for Anti-21 saline, n = 3 for Ang II saline, and n = 5 for Anti-21 Ang II. (J) Real-time RT-PCR analysis of miR-21 expression in cardiac tissue of animals after the indicated treatments using untreated C57BL/6 cardiac tissue as control (Ctrl).