Stress-dependent cardiac remodeling occurs in the absence of microRNA-21 in mice
David M. Patrick, Rusty L. Montgomery, Xiaoxia Qi, Susanna Obad, Sakari Kauppinen, Joseph A. Hill, Eva van Rooij, Eric N. Olson
David M. Patrick, Rusty L. Montgomery, Xiaoxia Qi, Susanna Obad, Sakari Kauppinen, Joseph A. Hill, Eva van Rooij, Eric N. Olson
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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

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Figure 3

Cardiac stress response after antimiR-21 treatment.

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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).