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WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

Huimei Chen1, Aida Moreno-Moral1, Francesco Pesce2

  • 1Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 169857, Republic of Singapore.

Nature Communications
|August 11, 2019
PubMed

Insights

WWP2, a specific E3 ubiquitin ligase isoform, drives cardiac fibrosis by regulating a pro-fibrotic gene network. Inhibiting this WWP2 isoform improves cardiac function and reduces fibrosis in disease models.

Area of Science:

  • Cardiovascular Biology
  • Molecular Genetics
  • Systems Genetics

Background:

  • Cardiac fibrosis is a common pathology leading to heart failure in various heart diseases.
  • Identifying the molecular regulators of cardiac fibrosis is crucial for therapeutic development.

Purpose of the Study:

  • To identify a pro-fibrotic gene network in diseased hearts.
  • To elucidate the role of the E3 ubiquitin ligase WWP2 in regulating this network and cardiac fibrosis.

Main Methods:

  • Systems genetics approach to identify gene networks.
  • Utilized transgenic mouse models (cardiac-specific WWP2 N-terminal deletion).
  • In vitro studies using primary cardiac fibroblasts and TGFβ1 stimulation.

Main Results:

  • Identified a conserved pro-fibrotic gene network regulated by WWP2, specifically its N-terminal isoform.
  • WWP2 positively regulates pro-fibrotic markers and extracellular matrix genes in cardiac fibroblasts.
  • WWP2 mediates TGFβ1-induced SMAD2 nuclear translocation and transcriptional activity, promoting fibrosis.

Conclusions:

  • The WWP2 N-terminal isoform is a key regulator of cardiac fibrosis across diverse heart conditions.
  • Targeting WWP2 offers a potential therapeutic strategy to mitigate cardiac fibrosis and improve cardiac function.

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