Cardiac myocyte apoptosis provokes adverse cardiac remodeling in transgenic mice with targeted TNF overexpression.
Although cardiac myocyte apoptosis has been detected in explanted hearts from patients with end-stage dilated and ischemic cardiomyopathy, the relative contribution of apoptotic cell death to left ventricular (LV) remodeling and cardiac decompensation is not known. To determine whether progressive cardiac myocyte apoptosis contributes to the transition from a hypertrophic to a dilated cardiac phenotype that is observed in transgenic myosin heavy chain secreted TNF (MHCsTNF) mice with cardiac restricted overexpression of tumor necrosis factor (TNF), we assessed cardiac myocyte apoptosis (using a DNA ligase technique) in MHCsTNF mice and littermate control mice in relation to serial changes in LV structure, which was assessed using MRI. The prevalence of cardiac myocyte apoptosis increased progressively from 4 to 12 wk as the hearts of the MHCsTNF mice underwent the transition from a concentric hypertrophic to a dilated cardiac phenotype. Treatment of the MHCsTNF mice with the broad-based caspase inhibitor N-[(1,3-dimethylindole-2-carbonyl)-valinyl]-3-amino4-oxo-5-fluoropentanoic acid significantly decreased cardiac myocyte apoptosis and significantly attenuated LV wall thinning and adverse cardiac remodeling. Additional studies suggested that the TNF-induced decrease in Bcl-2 expression and activation of the intrinsic mitochondrial death pathway were responsible for the cardiac myocyte apoptosis observed in the MHCsTNF mice. These studies show that progressive cardiac myocyte apoptosis is sufficient to contribute to adverse cardiac remodeling in the adult mammalian heart through progressive LV wall thinning.
Winters Center for Heart Failure Research, Baylor College of Medicine, and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas 77030, USA.
David
D
Engel
Ronald
R
Peshock
Robert C
RC
Armstong
Natarajan
N
Sivasubramanian
Douglas L
DL
Mann
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D004247:DNA; D011088:DNA Ligases / Q000378:metabolism; D015870:Gene Expression; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D032383:Myocytes, Cardiac / Q000502:physiology* / Q000648:ultrastructure; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000187:drug effects
D015853:Cysteine Proteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D045304:Cytochromes c; D004247:DNA; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D011088:DNA Ligases