A mechanistic role for cardiac myocyte apoptosis in heart failure
Detlef Wencker, … , Robert C. Armstrong, Richard N. Kitsis
Detlef Wencker, … , Robert C. Armstrong, Richard N. Kitsis
Published May 15, 2003
Citation Information: J Clin Invest. 2003;111(10):1497-1504. https://doi.org/10.1172/JCI17664.
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Article Cardiology

A mechanistic role for cardiac myocyte apoptosis in heart failure

Abstract

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 105 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 105 nuclei, compared with 1.5 myocytes per 105 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.

Authors

Detlef Wencker, Madhulika Chandra, Khanh Nguyen, Wenfeng Miao, Stavros Garantziotis, Stephen M. Factor, Jamshid Shirani, Robert C. Armstrong, Richard N. Kitsis

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Figure 1

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Expression of a conditionally active caspase-8 allele in the hearts of t...
Expression of a conditionally active caspase-8 allele in the hearts of transgenic mice. (a) Structure of the transgene protein and strategy for its activation. M, myristoylation signal; FKBP, human FKBP-12 (pk mutant); p20 and p10, 20- and 10-kDa domains, respectively, of human procaspase-8; HA, hemagglutinin tag; FK1012, dimerizer (see text). Cysteine 360, a residue essential for caspase activity, is shown. (b) Southern blot analysis of EcoRI-digested genomic DNA from WT mice and two of the ten transgenic lines generated. The probe, an EcoRI-XbaI mouse α-cardiac myosin heavy chain genomic fragment, identified a 3.6-kb transgene fragment and a 2.5-kb fragment of the endogenous α-cardiac myosin heavy chain. (c) Immunoblot analysis using an antibody against human caspase-8, showing transgene protein expression in the hearts of the most highly expressing (line 7) and least highly expressing (line 169) lines at 3 weeks of age. Levels of the point-mutated transgene protein in the hearts of line C360A mice are similar to those of the catalytically active transgene protein in the hearts of line 7 mice. The transgene protein was not detectable in a survey of other organs, as expected with the cardiac myocyte–specific α-cardiac myosin heavy chain promoter (not shown). The lower portion of the blot was reacted with an antibody against mouse tubulin as a loading control.