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Transforming growth factor β-activated kinase 1 signaling pathway critically regulates myocardial survival and

Lei Li1, Yi Chen1, Jessica Doan1

  • 1From the Department of Physiology and Biophysics, University of Washington, Seattle, WA (L.L., Y.C., J.D., J.M., Q.L.); and Howard Hughes Medical Institute, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.).

Circulation
|October 4, 2014
PubMed
Abstract

Insights

Transforming growth factor β-activated kinase 1 (TAK1) is essential for heart health. Its absence triggers programmed necrosis (necroptosis), leading to heart failure and adverse remodeling in mice.

Area of Science:

  • Cardiovascular Biology
  • Cell Death Mechanisms
  • Molecular Signaling

Background:

  • Programmed necrosis (necroptosis) is crucial in development and disease, but its cardiac regulation is unclear.
  • The role of necroptosis in myocardial remodeling and heart failure requires further investigation.

Purpose of the Study:

  • To investigate the role of transforming growth factor β-activated kinase 1 (TAK1) in regulating cardiac necroptosis.
  • To elucidate the molecular mechanisms by which TAK1 influences myocardial remodeling and heart failure.

Main Methods:

  • Cardiac-specific gene ablation of Map3k7 (encoding TAK1) in mice.
  • Analysis of myocyte apoptosis and necroptosis.
  • Assessment of myocardial remodeling and heart failure markers.
  • Investigation of tumor necrosis factor receptor-1 (TNFR1) signaling pathways.

Main Results:

  • Cardiac-specific Map3k7 ablation induced spontaneous apoptosis and necroptosis, causing adverse remodeling and heart failure.
  • These effects were dependent on TNFR1 signaling.
  • TAK1 acts as a molecular switch in TNFR1 signaling, regulating the formation of cell death complexes involving RIP1, FADD, and caspase 8.
  • Inhibition of RIP1 or RIP3 ameliorated necroptotic cell death and heart failure in TAK1-deficient mice.

Conclusions:

  • TAK1 is a critical survival factor in the heart, directly inhibiting necroptosis.
  • TAK1 is essential for maintaining myocardial homeostasis and preventing adverse remodeling.
  • Targeting TAK1-mediated necroptosis pathways may offer therapeutic strategies for heart failure.
Keywords:
apoptosisheart failuremyocytes, cardiacnecrosissignal transductionventricular remodeling

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