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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Activation of the caspase transgene in vivo results in massive cardiac m...
Activation of the caspase transgene in vivo results in massive cardiac myocyte apoptosis and death of the animals. (a) Mortality following intraperitoneal administration of vehicle alone (81.9% polyethylene glycol 400, 9.1% Tween-80, 9% dimethylacetate) or FK1012H2 (30 mg/kg in the vehicle) to 3-week-old WT mice and transgenic line 7, 169, and C360A mice. Animals were observed for death for 7 days following FK1012H2 administration. (b) Inverse dose-dependence of the time to death following intraperitoneal administration of the indicated doses of FK1012H2 to WT or transgenic line 7 (TG) mice. Animals were observed for death for 7 days following FK1012H2 administration, with no deaths occurring in the WT group. (c) Caspase inhibition delays time to death following transgene activation. Vehicle (0.9% saline) or the polycaspase inhibitor IDN 1965 (12 mg/kg in vehicle) was administered intraperitoneally to line 7 transgenic mice 45 minutes before FK1012H2 (30 mg/kg intraperitoneally) and every 4 hours thereafter as indicated by the triangles. Bars represent the survival times of individual animals that received vehicle or IDN 1965. Animals were observed for death until all had died. *P < 0.0001. (d) Activation of the transgene caspase by FK1012H2. Immunoblot of cardiac homogenates from WT and transgenic line 7, 169, and C360A mice treated 1.5 hours earlier with vehicle or FK1012H2 (30 mg/kg intraperitoneally). Processing of procaspase-8 is indicated by disappearance of the uncleaved moiety; cleavage fragments are not reliably detected in tissue homogenates, presumably because of rapid degradation. The lower portion of the blot was reacted with an antibody against mouse tubulin as a loading control. (e) Induction of cardiac apoptosis by FK1012H2. Genomic DNA from the hearts of WT and transgenic line 7 mice 1 hour after the administration of vehicle or FK1012H2 (30 mg/kg i.v.) was size-fractionated on an agarose gel containing ethidium bromide. (f) TUNEL analysis of FK1012H2-induced apoptosis. Paraffin-embedded sections of hearts from WT and line 7 transgenic mice 1 hour after administration of vehicle or FK1012H2 (30 mg/kg i.v.). TUNEL-positive cells were primarily myocytes, but additional unidentified cells were also present that may represent degenerating myocytes or infiltrating inflammatory cells due to magnitude and rapidity of the death. Bar, 20 μM.