A mechanistic role for cardiac myocyte apoptosis in heart failure.
Heart failure is a common, lethal condition whose pathogenesis is poorly understood. Recent studies have identified low levels of myocyte apoptosis (80-250 myocytes per 10(5) nuclei) in failing human hearts. It remains unclear, however, whether this cell death is a coincidental finding, a protective process, or a causal component in pathogenesis. Using transgenic mice that express a conditionally active caspase exclusively in the myocardium, we demonstrate that very low levels of myocyte apoptosis (23 myocytes per 10(5) nuclei, compared with 1.5 myocytes per 10(5) nuclei in controls) are sufficient to cause a lethal, dilated cardiomyopathy. Interestingly, these levels are four- to tenfold lower than those observed in failing human hearts. Conversely, inhibition of cardiac myocyte death in this murine model largely prevents the development of cardiac dilation and contractile dysfunction, the hallmarks of heart failure. To our knowledge, these data provide the first direct evidence that myocyte apoptosis may be a causal mechanism of heart failure, and they suggest that inhibition of this cell death process may constitute the basis for novel therapies.
Wencker
Detlef
D
Department of Medicine (Molecular Cardiology), Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Chandra
Madhulika
M
Nguyen
Khanh
K
Miao
Wenfeng
W
Garantziotis
Stavros
S
Factor
Stephen M
SM
Shirani
Jamshid
J
Armstrong
Robert C
RC
Kitsis
Richard N
RN
D000818:Animals; D017209:Apoptosis; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000235:genetics; D019281:Dimerization; D004195:Disease Models, Animal; D018450:Disease Progression; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology; D006333:Heart Failure / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009928:Organ Specificity / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins / Q000235:genetics; D019076:Transgenes
D020536:Enzyme Activators; C084260:FK 1012; D011993:Recombinant Fusion Proteins; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D022021:Tacrolimus Binding Proteins; D016559:Tacrolimus