Inhibition of Cardiac Myocyte Apoptosis Improves Cardiac Function and Abolishes Mortality in the Peripartum Cardiomyopathy of Gαq Transgenic Mice

Yukihiro Hayakawa, Madhulika Chandra, Wenfeng Miao, Jamshid Shirani, Joan Heller Brown, Gerald W. Dorn, Robert C. Armstrong, Richard N. Kitsis

Research output: Contribution to journalArticle

182 Citations (Scopus)

Abstract

Background-Although the occurrence of cardiac myocyte apoptosis during heart failure has been documented, its importance in pathogenesis is unknown. Transgenic mice with cardiac-restricted overexpression of Gαq exhibit a lethal, peripartum cardiomyopathy accompanied by apoptosis. To test whether apoptosis is causally linked to heart failure, we assessed whether inhibiting this cell death would improve left ventricular function and survival in the Gαq peripartum cardiomyopathy model. Methods and Results-The potent polycaspase inhibitor IDN-1965 or vehicle was administered subcutaneously to Gαq mice by osmotic minipump beginning on day 12 of pregnancy and continuing through euthanasia at day 14 postpartum. As expected, IDN-1965 markedly suppressed cardiac caspase-3-like activity (86.5%; P<0.01), accompanied by reduction in the frequency of cardiac myocyte apoptosis from 1.9±0.3% to 0.2±0.1% (P<0.01). Animals receiving IDN-1965 exhibited significant improvements in left ventricular end-diastolic dimension (vehicle, 4.7±0.1 mm; IDN-1965, 4.2±0.1 mm; P<0.01), fractional shortening (vehicle, 30.7±1.2%; IDN-1965, 38.9±1.0%; P<0.01), positive (vehicle, 3972±412; IDN-1965, 5870±295; P<0.01) and negative (vehicle, 2365±213; IDN-1965, 3413±201; P<0.01) dP/dt, and complete suppression of mortality (vehicle, 6 of 20 died; IDN-1965, 0 of 14 died; P<0.05). Conclusions-Reduction in cardiac myocyte apoptosis by caspase inhibition improved left ventricular function and survival in pregnant Gαq mice. These data indicate that cardiac myocyte apoptosis plays a causal role in the pathogenesis of cardiomyopathy in this model. Caspase inhibition may provide a novel therapeutic target for heart failure.

Original languageEnglish (US)
Pages (from-to)3036-3041
Number of pages6
JournalCirculation
Volume108
Issue number24
DOIs
StatePublished - Dec 16 2003

Fingerprint

Peripartum Period
Cardiomyopathies
Cardiac Myocytes
Transgenic Mice
Apoptosis
Mortality
Heart Failure
Caspases
Left Ventricular Function
Euthanasia
N-((1,3-dimethylindole-2-carbonyl)-valinyl)-3-amino-4-oxo-5-fluoropentanoic acid
Caspase 3
Postpartum Period
Cell Death
Pregnancy

Keywords

  • Apoptosis
  • Cardiomyopathy
  • Caspases

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Inhibition of Cardiac Myocyte Apoptosis Improves Cardiac Function and Abolishes Mortality in the Peripartum Cardiomyopathy of Gαq Transgenic Mice. / Hayakawa, Yukihiro; Chandra, Madhulika; Miao, Wenfeng; Shirani, Jamshid; Brown, Joan Heller; Dorn, Gerald W.; Armstrong, Robert C.; Kitsis, Richard N.

In: Circulation, Vol. 108, No. 24, 16.12.2003, p. 3036-3041.

Research output: Contribution to journalArticle

Hayakawa, Yukihiro ; Chandra, Madhulika ; Miao, Wenfeng ; Shirani, Jamshid ; Brown, Joan Heller ; Dorn, Gerald W. ; Armstrong, Robert C. ; Kitsis, Richard N. / Inhibition of Cardiac Myocyte Apoptosis Improves Cardiac Function and Abolishes Mortality in the Peripartum Cardiomyopathy of Gαq Transgenic Mice. In: Circulation. 2003 ; Vol. 108, No. 24. pp. 3036-3041.
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abstract = "Background-Although the occurrence of cardiac myocyte apoptosis during heart failure has been documented, its importance in pathogenesis is unknown. Transgenic mice with cardiac-restricted overexpression of Gαq exhibit a lethal, peripartum cardiomyopathy accompanied by apoptosis. To test whether apoptosis is causally linked to heart failure, we assessed whether inhibiting this cell death would improve left ventricular function and survival in the Gαq peripartum cardiomyopathy model. Methods and Results-The potent polycaspase inhibitor IDN-1965 or vehicle was administered subcutaneously to Gαq mice by osmotic minipump beginning on day 12 of pregnancy and continuing through euthanasia at day 14 postpartum. As expected, IDN-1965 markedly suppressed cardiac caspase-3-like activity (86.5{\%}; P<0.01), accompanied by reduction in the frequency of cardiac myocyte apoptosis from 1.9±0.3{\%} to 0.2±0.1{\%} (P<0.01). Animals receiving IDN-1965 exhibited significant improvements in left ventricular end-diastolic dimension (vehicle, 4.7±0.1 mm; IDN-1965, 4.2±0.1 mm; P<0.01), fractional shortening (vehicle, 30.7±1.2{\%}; IDN-1965, 38.9±1.0{\%}; P<0.01), positive (vehicle, 3972±412; IDN-1965, 5870±295; P<0.01) and negative (vehicle, 2365±213; IDN-1965, 3413±201; P<0.01) dP/dt, and complete suppression of mortality (vehicle, 6 of 20 died; IDN-1965, 0 of 14 died; P<0.05). Conclusions-Reduction in cardiac myocyte apoptosis by caspase inhibition improved left ventricular function and survival in pregnant Gαq mice. These data indicate that cardiac myocyte apoptosis plays a causal role in the pathogenesis of cardiomyopathy in this model. Caspase inhibition may provide a novel therapeutic target for heart failure.",
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AU - Miao, Wenfeng

AU - Shirani, Jamshid

AU - Brown, Joan Heller

AU - Dorn, Gerald W.

AU - Armstrong, Robert C.

AU - Kitsis, Richard N.

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N2 - Background-Although the occurrence of cardiac myocyte apoptosis during heart failure has been documented, its importance in pathogenesis is unknown. Transgenic mice with cardiac-restricted overexpression of Gαq exhibit a lethal, peripartum cardiomyopathy accompanied by apoptosis. To test whether apoptosis is causally linked to heart failure, we assessed whether inhibiting this cell death would improve left ventricular function and survival in the Gαq peripartum cardiomyopathy model. Methods and Results-The potent polycaspase inhibitor IDN-1965 or vehicle was administered subcutaneously to Gαq mice by osmotic minipump beginning on day 12 of pregnancy and continuing through euthanasia at day 14 postpartum. As expected, IDN-1965 markedly suppressed cardiac caspase-3-like activity (86.5%; P<0.01), accompanied by reduction in the frequency of cardiac myocyte apoptosis from 1.9±0.3% to 0.2±0.1% (P<0.01). Animals receiving IDN-1965 exhibited significant improvements in left ventricular end-diastolic dimension (vehicle, 4.7±0.1 mm; IDN-1965, 4.2±0.1 mm; P<0.01), fractional shortening (vehicle, 30.7±1.2%; IDN-1965, 38.9±1.0%; P<0.01), positive (vehicle, 3972±412; IDN-1965, 5870±295; P<0.01) and negative (vehicle, 2365±213; IDN-1965, 3413±201; P<0.01) dP/dt, and complete suppression of mortality (vehicle, 6 of 20 died; IDN-1965, 0 of 14 died; P<0.05). Conclusions-Reduction in cardiac myocyte apoptosis by caspase inhibition improved left ventricular function and survival in pregnant Gαq mice. These data indicate that cardiac myocyte apoptosis plays a causal role in the pathogenesis of cardiomyopathy in this model. Caspase inhibition may provide a novel therapeutic target for heart failure.

AB - Background-Although the occurrence of cardiac myocyte apoptosis during heart failure has been documented, its importance in pathogenesis is unknown. Transgenic mice with cardiac-restricted overexpression of Gαq exhibit a lethal, peripartum cardiomyopathy accompanied by apoptosis. To test whether apoptosis is causally linked to heart failure, we assessed whether inhibiting this cell death would improve left ventricular function and survival in the Gαq peripartum cardiomyopathy model. Methods and Results-The potent polycaspase inhibitor IDN-1965 or vehicle was administered subcutaneously to Gαq mice by osmotic minipump beginning on day 12 of pregnancy and continuing through euthanasia at day 14 postpartum. As expected, IDN-1965 markedly suppressed cardiac caspase-3-like activity (86.5%; P<0.01), accompanied by reduction in the frequency of cardiac myocyte apoptosis from 1.9±0.3% to 0.2±0.1% (P<0.01). Animals receiving IDN-1965 exhibited significant improvements in left ventricular end-diastolic dimension (vehicle, 4.7±0.1 mm; IDN-1965, 4.2±0.1 mm; P<0.01), fractional shortening (vehicle, 30.7±1.2%; IDN-1965, 38.9±1.0%; P<0.01), positive (vehicle, 3972±412; IDN-1965, 5870±295; P<0.01) and negative (vehicle, 2365±213; IDN-1965, 3413±201; P<0.01) dP/dt, and complete suppression of mortality (vehicle, 6 of 20 died; IDN-1965, 0 of 14 died; P<0.05). Conclusions-Reduction in cardiac myocyte apoptosis by caspase inhibition improved left ventricular function and survival in pregnant Gαq mice. These data indicate that cardiac myocyte apoptosis plays a causal role in the pathogenesis of cardiomyopathy in this model. Caspase inhibition may provide a novel therapeutic target for heart failure.

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