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Protease activated receptor-2 contributes to heart failure

Silvio Antoniak1, Erica M Sparkenbaugh, Michael Tencati

  • 1UNC McAllister Heart Institute, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.

Plos One
|December 7, 2013
PubMed

Insights

Protease-activated receptor-2 (PAR-2) signaling drives heart hypertrophy and failure. Inhibiting PAR-2 may offer a therapeutic strategy for preventing cardiac remodeling and improving function after heart attacks.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • G protein-coupled receptor signaling

Background:

  • Heart failure is a significant global health issue.
  • G protein-coupled receptors, particularly protease-activated receptors (PARs), are implicated in cardiac hypertrophy and failure.
  • PAR-2 activation on cardiomyocytes promotes hypertrophic growth and contributes to adverse cardiac remodeling post-myocardial infarction.

Purpose of the Study:

  • To investigate the role of PAR-2 in cardiomyocyte hypertrophy, fibrosis, and heart failure.
  • To elucidate the signaling pathways involved in PAR-2-mediated cardiac effects.
  • To evaluate the therapeutic potential of targeting PAR-2 in myocardial infarction.

Main Methods:

  • Utilized cultured rat and mouse neonatal cardiomyocytes to assess PAR-2 effects on hypertrophy and gene expression.
  • Employed cardiomyocyte-specific PAR-2 overexpression in mice to model cardiac pathology.
  • Generated a mouse model of myocardial infarction using permanent coronary artery ligation and assessed the impact of PAR-2 deficiency.

Main Results:

  • PAR-2 activation induced hypertrophic growth in cardiomyocytes via MEK1/2 and p38 signaling.
  • PAR-2 increased expression of the pro-fibrotic chemokine MCP-1 in cardiomyocytes.
  • Cardiomyocyte-specific PAR-2 overexpression led to heart hypertrophy, fibrosis, inflammation, and heart failure in mice.
  • PAR-2 deficiency attenuated cardiac remodeling and improved function following myocardial infarction, independent of infarct size.

Conclusions:

  • PAR-2 signaling is a key driver of cardiac hypertrophy and heart failure.
  • Targeting PAR-2 represents a potential therapeutic strategy for managing heart disease and improving outcomes after myocardial infarction.

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