New Molecular Mechanisms for Cardiovascular Disease : Transcriptional Pathways and Novel Therapeutic Targets in Heart Failure

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Author(s)

Abstract

Genetic remodeling contributes to the progression of heart failure by affecting myocardial cellular function and survival. In our investigation of the transcriptional regulation of cardiac gene expression, we found several transcriptional pathways involved in pathological cardiac remodeling. A transcriptional repressor, neuron-restrictive silencer factor (NRSF), regulates expression of multiple fetal cardiac genes through the activity of histone deacetylases (HDACs). Inhibition of NRSF in the heart results in cardiac dysfunction and sudden arrhythmic death accompanied by re-expression of a number of fetal genes, including those encoding fetal ion channels, such as the T-type Ca<SUP>2+</SUP> channel. In the pathological calcineurin – nuclear factor of activated T-cells (NFAT) signaling pathway, transient receptor potential cation channel, subfamily C, member 6 (TRPC6) is a key component of a Ca<SUP>2+</SUP>-dependent regulatory loop. Indeed, inhibition of TRPC significantly ameliorates this pathological process in a mouse model of cardiac hypertrophy. Moreover, we recently showed that myocardin-related transcription factor-A (MRTF-A), a co-activator of serum response factor (SRF), mediates prohypertrophic signaling by linking the small GTPase Rho-actin dynamics signaling pathway to cardiac gene transcription. Collectively, our studies have revealed the transcriptional network involved in the development of cardiac dysfunction and potential therapeutic targets for the treatment of heart failure.

Journal

  • Journal of Pharmacological Sciences

    Journal of Pharmacological Sciences 116(4), 337-342, 2011-08-20

    The Japanese Pharmacological Society

References:  40

Cited by:  2

Codes

  • NII Article ID (NAID)
    10029895482
  • NII NACSIS-CAT ID (NCID)
    AA11806667
  • Text Lang
    ENG
  • Article Type
    Journal Article
  • ISSN
    13478613
  • NDL Article ID
    11206880
  • NDL Source Classification
    ZS51(科学技術--薬学)
  • NDL Call No.
    Z53-D199
  • Data Source
    CJP  CJPref  NDL  J-STAGE 
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