title: Inhibition of cardiac myocyte apoptosis improves cardiac function and abolishes mortality in the peripartum cardiomyopathy of Galpha(q) transgenic mice.
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 Galpha(q) 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 Galpha(q) peripartum cardiomyopathy model.
  
  
  RESULTS
  The potent polycaspase inhibitor IDN-1965 or vehicle was administered subcutaneously to Galpha(q) 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 Galpha(q) 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.
authors.affiliation: Program in Molecular Cardiology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Hayakawa
authors.forename: Madhulika
authors.initials: M
authors.lastname: Chandra
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Miao
authors.forename: Jamshid
authors.initials: J
authors.lastname: Shirani
authors.forename: Joan Heller
authors.initials: JH
authors.lastname: Brown
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
authors.forename: Robert C
authors.initials: RC
authors.lastname: Armstrong
authors.forename: Richard N
authors.initials: RN
authors.lastname: Kitsis
mesh_terms: D000818:Animals; D017209:Apoptosis; D002311:Cardiomyopathy, Dilated / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005260:Female; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics*; D006352:Heart Ventricles / Q000000981:diagnostic imaging; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000473:pathology*; D009842:Oligopeptides / Q000494:pharmacology; D049590:Postpartum Period; D011247:Pregnancy; D016019:Survival Analysis; D014463:Ultrasonography; D016277:Ventricular Function, Left
chemical_list: D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D007211:Indoles; C118798:N-((1,3-dimethylindole-2-carbonyl)-valinyl)-3-amino-4-oxo-5-fluoropentanoic acid; D009842:Oligopeptides; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11