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

• Published in: The Journal of clinical investigation 2007-09, Vol.117 (9), p.2692-2701
• Main Authors: Haudek, Sandra B, Taffet, George E, Schneider, Michael D, Mann, Douglas L
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biomedical research; Caspases - metabolism; Cell death; Cytochromes c - metabolism; Cytochromes c - secretion; Enzyme Activation; Genetic aspects; Genetically modified mice; Health aspects; Humans; Hypertrophy - metabolism; Hypertrophy - pathology; Mice; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - secretion; Proto-Oncogene Proteins c-bcl-2 - metabolism; Tumor Necrosis Factor-alpha - metabolism; Ventricular Remodeling
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci29134

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.