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

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.

Pubmed ID: 19726871

Authors

  • Callis TE
  • Pandya K
  • Seok HY
  • Tang RH
  • Tatsuguchi M
  • Huang ZP
  • Chen JF
  • Deng Z
  • Gunn B
  • Shumate J
  • Willis MS
  • Selzman CH
  • Wang DZ

Journal

The Journal of clinical investigation

Publication Data

September 4, 2009

Associated Grants

None

Mesh Terms

  • Animals
  • Base Sequence
  • Cardiac Myosins
  • Cardiomegaly
  • DNA Primers
  • Gene Expression
  • Heart
  • Heart Conduction System
  • Introns
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • MicroRNAs
  • Molecular Sequence Data
  • Myosin Heavy Chains
  • Recombinant Fusion Proteins
  • Sequence Homology, Nucleic Acid