MicroRNA-31 promotes adverse cardiac remodeling and dysfunction in ischemic heart disease

Eliana Cecilia Martinez, Shera Lilyanna, Peipei Wang, Leah A Vardy, Xiaofei Jiang, Arunmozhiarasi Armugam, Kandiah Jeyaseelan, Mark Arthur Richards

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Rationale Myocardial infarction (MI) triggers a dynamic microRNA response with the potential of yielding therapeutic targets. Objective We aimed to identify novel aberrantly expressed cardiac microRNAs post-MI with potential roles in adverse remodeling in a rat model, and to provide post-ischemic therapeutic inhibition of a candidate pathological microRNA in vivo. Methods and results Following microRNA array profiling in rat hearts 2 and 14 days post-MI, we identified a time-dependent up-regulation of miR-31 compared to sham-operated rats. A progressive increase of miR-31 (up to 91.4 ± 11.3 fold) was detected in the infarcted myocardium by quantitative real-time PCR. Following target prediction analysis, reporter gene assays confirmed that miR-31 targets the 3´UTR of cardiac troponin-T (Tnnt2), E2F transcription factor 6 (E2f6), mineralocorticoid receptor (Nr3c2) and metalloproteinase inhibitor 4 (Timp4) mRNAs. In vitro, hypoxia and oxidative stress up-regulated miR-31 and suppressed target genes in cardiac cell cultures, whereas LNA-based oligonucleotide inhibition of miR-31 (miR-31i) reversed its repressive effect on target mRNAs. Therapeutic post-ischemic administration of miR-31i in rats silenced cardiac miR-31 and enhanced expression of target genes, while preserving cardiac structure and function at 2 and 4 weeks post-MI. Left ventricular ejection fraction (EF) improved by 10% (from day 2 to 30 post-MI) in miR-31i-treated rats, whereas controls receiving scrambled LNA inhibitor or placebo incurred a 17% deterioration in EF. miR-31i decreased end-diastolic pressure and infarct size; attenuated interstitial fibrosis in the remote myocardium and enhanced cardiac output. Conclusion miR-31 induction after MI is deleterious to cardiac function while its therapeutic inhibition in vivo ameliorates cardiac dysfunction and prevents the development of post-ischemic adverse remodeling.

Original languageEnglish
Pages (from-to)27-39
Number of pages13
JournalJournal of Molecular and Cellular Cardiology
Volume112
DOIs
Publication statusPublished - 1 Nov 2017

Keywords

  • Animal models
  • Heart failure
  • MicroRNAs
  • Myocardial infarction
  • Remodeling

Cite this

Martinez, E. C., Lilyanna, S., Wang, P., Vardy, L. A., Jiang, X., Armugam, A., ... Richards, M. A. (2017). MicroRNA-31 promotes adverse cardiac remodeling and dysfunction in ischemic heart disease. Journal of Molecular and Cellular Cardiology, 112, 27-39. https://doi.org/10.1016/j.yjmcc.2017.08.013
Martinez, Eliana Cecilia ; Lilyanna, Shera ; Wang, Peipei ; Vardy, Leah A ; Jiang, Xiaofei ; Armugam, Arunmozhiarasi ; Jeyaseelan, Kandiah ; Richards, Mark Arthur. / MicroRNA-31 promotes adverse cardiac remodeling and dysfunction in ischemic heart disease. In: Journal of Molecular and Cellular Cardiology. 2017 ; Vol. 112. pp. 27-39.
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title = "MicroRNA-31 promotes adverse cardiac remodeling and dysfunction in ischemic heart disease",
abstract = "Rationale Myocardial infarction (MI) triggers a dynamic microRNA response with the potential of yielding therapeutic targets. Objective We aimed to identify novel aberrantly expressed cardiac microRNAs post-MI with potential roles in adverse remodeling in a rat model, and to provide post-ischemic therapeutic inhibition of a candidate pathological microRNA in vivo. Methods and results Following microRNA array profiling in rat hearts 2 and 14 days post-MI, we identified a time-dependent up-regulation of miR-31 compared to sham-operated rats. A progressive increase of miR-31 (up to 91.4 ± 11.3 fold) was detected in the infarcted myocardium by quantitative real-time PCR. Following target prediction analysis, reporter gene assays confirmed that miR-31 targets the 3´UTR of cardiac troponin-T (Tnnt2), E2F transcription factor 6 (E2f6), mineralocorticoid receptor (Nr3c2) and metalloproteinase inhibitor 4 (Timp4) mRNAs. In vitro, hypoxia and oxidative stress up-regulated miR-31 and suppressed target genes in cardiac cell cultures, whereas LNA-based oligonucleotide inhibition of miR-31 (miR-31i) reversed its repressive effect on target mRNAs. Therapeutic post-ischemic administration of miR-31i in rats silenced cardiac miR-31 and enhanced expression of target genes, while preserving cardiac structure and function at 2 and 4 weeks post-MI. Left ventricular ejection fraction (EF) improved by 10{\%} (from day 2 to 30 post-MI) in miR-31i-treated rats, whereas controls receiving scrambled LNA inhibitor or placebo incurred a 17{\%} deterioration in EF. miR-31i decreased end-diastolic pressure and infarct size; attenuated interstitial fibrosis in the remote myocardium and enhanced cardiac output. Conclusion miR-31 induction after MI is deleterious to cardiac function while its therapeutic inhibition in vivo ameliorates cardiac dysfunction and prevents the development of post-ischemic adverse remodeling.",
keywords = "Animal models, Heart failure, MicroRNAs, Myocardial infarction, Remodeling",
author = "Martinez, {Eliana Cecilia} and Shera Lilyanna and Peipei Wang and Vardy, {Leah A} and Xiaofei Jiang and Arunmozhiarasi Armugam and Kandiah Jeyaseelan and Richards, {Mark Arthur}",
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Martinez, EC, Lilyanna, S, Wang, P, Vardy, LA, Jiang, X, Armugam, A, Jeyaseelan, K & Richards, MA 2017, 'MicroRNA-31 promotes adverse cardiac remodeling and dysfunction in ischemic heart disease' Journal of Molecular and Cellular Cardiology, vol. 112, pp. 27-39. https://doi.org/10.1016/j.yjmcc.2017.08.013

MicroRNA-31 promotes adverse cardiac remodeling and dysfunction in ischemic heart disease. / Martinez, Eliana Cecilia; Lilyanna, Shera; Wang, Peipei; Vardy, Leah A; Jiang, Xiaofei; Armugam, Arunmozhiarasi; Jeyaseelan, Kandiah; Richards, Mark Arthur.

In: Journal of Molecular and Cellular Cardiology, Vol. 112, 01.11.2017, p. 27-39.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - MicroRNA-31 promotes adverse cardiac remodeling and dysfunction in ischemic heart disease

AU - Martinez, Eliana Cecilia

AU - Lilyanna, Shera

AU - Wang, Peipei

AU - Vardy, Leah A

AU - Jiang, Xiaofei

AU - Armugam, Arunmozhiarasi

AU - Jeyaseelan, Kandiah

AU - Richards, Mark Arthur

PY - 2017/11/1

Y1 - 2017/11/1

N2 - Rationale Myocardial infarction (MI) triggers a dynamic microRNA response with the potential of yielding therapeutic targets. Objective We aimed to identify novel aberrantly expressed cardiac microRNAs post-MI with potential roles in adverse remodeling in a rat model, and to provide post-ischemic therapeutic inhibition of a candidate pathological microRNA in vivo. Methods and results Following microRNA array profiling in rat hearts 2 and 14 days post-MI, we identified a time-dependent up-regulation of miR-31 compared to sham-operated rats. A progressive increase of miR-31 (up to 91.4 ± 11.3 fold) was detected in the infarcted myocardium by quantitative real-time PCR. Following target prediction analysis, reporter gene assays confirmed that miR-31 targets the 3´UTR of cardiac troponin-T (Tnnt2), E2F transcription factor 6 (E2f6), mineralocorticoid receptor (Nr3c2) and metalloproteinase inhibitor 4 (Timp4) mRNAs. In vitro, hypoxia and oxidative stress up-regulated miR-31 and suppressed target genes in cardiac cell cultures, whereas LNA-based oligonucleotide inhibition of miR-31 (miR-31i) reversed its repressive effect on target mRNAs. Therapeutic post-ischemic administration of miR-31i in rats silenced cardiac miR-31 and enhanced expression of target genes, while preserving cardiac structure and function at 2 and 4 weeks post-MI. Left ventricular ejection fraction (EF) improved by 10% (from day 2 to 30 post-MI) in miR-31i-treated rats, whereas controls receiving scrambled LNA inhibitor or placebo incurred a 17% deterioration in EF. miR-31i decreased end-diastolic pressure and infarct size; attenuated interstitial fibrosis in the remote myocardium and enhanced cardiac output. Conclusion miR-31 induction after MI is deleterious to cardiac function while its therapeutic inhibition in vivo ameliorates cardiac dysfunction and prevents the development of post-ischemic adverse remodeling.

AB - Rationale Myocardial infarction (MI) triggers a dynamic microRNA response with the potential of yielding therapeutic targets. Objective We aimed to identify novel aberrantly expressed cardiac microRNAs post-MI with potential roles in adverse remodeling in a rat model, and to provide post-ischemic therapeutic inhibition of a candidate pathological microRNA in vivo. Methods and results Following microRNA array profiling in rat hearts 2 and 14 days post-MI, we identified a time-dependent up-regulation of miR-31 compared to sham-operated rats. A progressive increase of miR-31 (up to 91.4 ± 11.3 fold) was detected in the infarcted myocardium by quantitative real-time PCR. Following target prediction analysis, reporter gene assays confirmed that miR-31 targets the 3´UTR of cardiac troponin-T (Tnnt2), E2F transcription factor 6 (E2f6), mineralocorticoid receptor (Nr3c2) and metalloproteinase inhibitor 4 (Timp4) mRNAs. In vitro, hypoxia and oxidative stress up-regulated miR-31 and suppressed target genes in cardiac cell cultures, whereas LNA-based oligonucleotide inhibition of miR-31 (miR-31i) reversed its repressive effect on target mRNAs. Therapeutic post-ischemic administration of miR-31i in rats silenced cardiac miR-31 and enhanced expression of target genes, while preserving cardiac structure and function at 2 and 4 weeks post-MI. Left ventricular ejection fraction (EF) improved by 10% (from day 2 to 30 post-MI) in miR-31i-treated rats, whereas controls receiving scrambled LNA inhibitor or placebo incurred a 17% deterioration in EF. miR-31i decreased end-diastolic pressure and infarct size; attenuated interstitial fibrosis in the remote myocardium and enhanced cardiac output. Conclusion miR-31 induction after MI is deleterious to cardiac function while its therapeutic inhibition in vivo ameliorates cardiac dysfunction and prevents the development of post-ischemic adverse remodeling.

KW - Animal models

KW - Heart failure

KW - MicroRNAs

KW - Myocardial infarction

KW - Remodeling

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