TNF provokes cardiomyocyte apoptosis and cardiac remodeling through activation of multiple cell death pathways

J Clin Invest. 2007 Sep;117(9):2692-701. doi: 10.1172/JCI29134.

Abstract

Transgenic mice with cardiac-restricted overexpression of secretable TNF (MHCsTNF) develop progressive LV wall thinning and dilation accompanied by an increase in cardiomyocyte apoptosis and a progressive loss of cytoprotective Bcl-2. To test whether cardiac-restricted overexpression of Bcl-2 would prevent adverse cardiac remodeling, we crossed MHCsTNF mice with transgenic mice harboring cardiac-restricted overexpression of Bcl-2. Sustained TNF signaling resulted in activation of the intrinsic cell death pathway, leading to increased cytosolic levels of cytochrome c, Smac/Diablo and Omi/HtrA2, and activation of caspases -3 and -9. Cardiac-restricted overexpression of Bcl-2 blunted activation of the intrinsic pathway and prevented LV wall thinning; however, Bcl-2 only partially attenuated cardiomyocyte apoptosis. Subsequent studies showed that c-FLIP was degraded, that caspase-8 was activated, and that Bid was cleaved to t-Bid, suggesting that the extrinsic pathway was activated concurrently in MHCsTNF hearts. As expected, cardiac Bcl-2 overexpression had no effect on extrinsic signaling. Thus, our results suggest that sustained inflammation leads to activation of multiple cell death pathways that contribute to progressive cardiomyocyte apoptosis; hence the extent of such programmed myocyte cell death is a critical determinant of adverse cardiac remodeling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis*
  • Caspases / metabolism
  • Cytochromes c / metabolism
  • Enzyme Activation
  • Humans
  • Hypertrophy / metabolism
  • Hypertrophy / pathology
  • Mice
  • Myocytes, Cardiac / cytology*
  • Myocytes, Cardiac / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Tumor Necrosis Factor-alpha / metabolism*
  • Ventricular Remodeling*

Substances

  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Necrosis Factor-alpha
  • Cytochromes c
  • Caspases