MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice

Thomas E. Callis, Kumar Pandya, Young Seok Hee, Ru Hang Tang, Mariko Tatsuguchi, Zhan Peng Huang, Jian Fu Chen, Zhongliang Deng, Bronwyn Gunn, Janelle Shumate, Monte S. Willis, Craig H. Selzman, Da Zhi Wang

Research output: Contribution to journalArticlepeer-review

596 Scopus citations

Abstract

MicroRNAs (miRNAs) are a class of small noncoding RNAs that have gained status as important regulators of gene expression. Here, we investigated the function and molecular mechanisms of the miR-208 family of miRNAs in adult mouse heart physiology. We found that miR-208a, which is encoded within an intron of α-cardiac muscle myosin heavy chain gene (Myh6), was actually a member of a miRNA family that also included miR-208b, which was determined to be encoded within an intron of β-cardiac muscle myosin heavy chain gene (Myh7). These miRNAs were differentially expressed in the mouse heart, paralleling the expression of their host genes. Transgenic overexpression of miR-208a in the heart was sufficient to induce hypertrophic growth in mice, which resulted in pronounced repression of the miR-208 regulatory targets thyroid hormone-associated protein 1 and myostatin, 2 negative regulators of muscle growth and hypertrophy. Studies of the miR-208a Tg mice indicated that miR-208a expression was sufficient to induce arrhythmias. Furthermore, analysis of mice lacking miR-208a indicated that miR-208a was required for proper cardiac conduction and expression of the cardiac transcription factors homeodomain-only protein and GATA4 and the gap junction protein connexin 40. Together, our studies uncover what we believe are novel miRNA-dependent mechanisms that modulate cardiac hypertrophy and electrical conduction.

Original languageEnglish (US)
Pages (from-to)2772-2786
Number of pages15
JournalJournal of Clinical Investigation
Volume119
Issue number9
DOIs
StatePublished - Sep 1 2009

ASJC Scopus subject areas

  • Medicine(all)

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