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- Title
MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice.
- Authors
Callis, Thomas E; Pandya, Kumar; Seok, Hee Young; Tang, Ru-Hang; Tatsuguchi, Mariko; Huang, Zhan-Peng; Chen, Jian-Fu; Deng, Zhongliang; Gunn, Bronwyn; Shumate, Janelle; Willis, Monte S; Selzman, Craig H; Wang, Da-Zhi
- 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 alpha-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 beta-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.
- Publication
The Journal of clinical investigation, 2009, Vol 119, Issue 9, p2772
- ISSN
1558-8238
- Publication type
Journal Article
- DOI
10.1172/JCI36154