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Published on: September 14, 2021

TNF-alpha-mediated signal transduction pathway is a major determinant of apoptosis in dilated cardiomyopathy

Samarjit Das1, Andrea P Babick, Yan-Jun Xu

  • 1Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Center and Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.

Journal of Cellular and Molecular Medicine
|September 17, 2009
PubMed

Insights

Dilated cardiomyopathy in J2N-k hamsters involves heart failure and apoptosis. Tumor necrosis factor-alpha (TNF-alpha) and protein kinase C (PKC) signaling pathways activate pro-apoptotic proteins, contributing to cardiac dysfunction.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Animal Models of Disease

Background:

  • Dilated cardiomyopathy (DCM) is a significant cause of heart failure.
  • The J2N-k hamster strain is a recognized model for studying DCM.
  • Mechanisms of apoptosis in this hamster model were previously unexamined.

Purpose of the Study:

  • To investigate the role of apoptosis in cardiac dysfunction in J2N-k cardiomyopathic hamsters.
  • To explore the involvement of the tumor necrosis factor-alpha (TNF-alpha) signaling pathway.
  • To identify specific pro- and anti-apoptotic protein alterations.

Main Methods:

  • Echocardiography was used to assess cardiac function in 31-week-old hamsters.
  • Protein levels of TNF-alpha, caspases, protein kinase C (PKC) isozymes, and key signaling molecules (MAPK, NF-kappaB, BAD, Bcl-2) were analyzed.
  • Apoptosis markers were quantified in cardiac tissue.

Main Results:

  • Echocardiography revealed ventricular dilation and reduced cardiac output without hypertrophy.
  • Increased TNF-alpha and apoptosis correlated with elevated PKC-alpha, PKC-epsilon, caspase-3, and caspase-9.
  • Key signaling pathway changes included increased p38 MAPK and NF-kappaB, and decreased Erk1/2, BAD, and Bcl-2.

Conclusions:

  • Cardiac dysfunction in this DCM model is associated with increased apoptosis.
  • The TNF-alpha and PKC signaling pathways appear to mediate apoptosis.
  • Activation of p38 MAPK and deactivation of Erk1/2 pathways contribute to the observed cardiac pathology.

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