Published online before print November 24, 2003, doi: 10.1161/01.CIR.0000101920.72665.58
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2003;108:3036.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Inhibition of Cardiac Myocyte Apoptosis Improves Cardiac Function and Abolishes Mortality in the Peripartum Cardiomyopathy of G
q Transgenic Mice
From the Program in Molecular Cardiology, Department of Medicine (Y.H., M.C., W.M., J.S., R.N.K.), and the Department of Cell Biology (Y.H., R.N.K.), Albert Einstein College of Medicine, Bronx, NY; the Department of Pharmacology, University of California San Diego, La Jolla (J.H.B.); the Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio (G.W.D.); and Idun Pharmaceuticals, San Diego, Calif (R.C.A.).
Correspondence to Richard N. Kitsis, MD, Program in Molecular Cardiology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461. E-mail kitsis{at}aecom.yu.edu
Received March 4, 2003; revision received August 8, 2003; accepted August 8, 2003.
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 G
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 Gq peripartum cardiomyopathy model.
Methods and Results— The potent polycaspase inhibitor IDN-1965 or vehicle was administered subcutaneously to Gq 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 Gq 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.
Key Words: apoptosis • caspases • cardiomyopathy
Related Article:
Circulation 2003 108: 2954-2956.
This article has been cited by other articles:
 |
|
 |
|
  J. G. Williams, C. Ojaimi, K. Qanud, S. Zhang, X. Xu, F. A. Recchia, and T. H. Hintze Coronary nitric oxide production controls cardiac substrate metabolism during pregnancy in the dog Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2516 - H2523. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Diwan, J. Wansapura, F. M. Syed, S. J. Matkovich, J. N. Lorenz, and G. W. Dorn II Nix-Mediated Apoptosis Links Myocardial Fibrosis, Cardiac Remodeling, and Hypertrophy Decompensation Circulation, January 22, 2008; 117(3): 396 - 404. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-Z. Li, D.-Y. Lu, W.-Q. Tan, J.-X. Wang, and P.-F. Li p53 Initiates Apoptosis by Transcriptionally Targeting the Antiapoptotic Protein ARC Mol. Cell. Biol., January 15, 2008; 28(2): 564 - 574. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. B. Liggett, R. J. Kelly, R. R. Parekh, S. J. Matkovich, B. J. Benner, H. S. Hahn, F. M. Syed, A. S. Galvez, K. L. Case, N. McGuire, et al. A functional polymorphism of the G{alpha}q (GNAQ) gene is associated with accelerated mortality in African-American heart failure Hum. Mol. Genet., November 15, 2007; 16(22): 2740 - 2750. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. Watson, J. E. B. Reusch, S. A. McCune, L. A. Leinwand, S. W. Luckey, J. P. Konhilas, D. A. Brown, A. J. Chicco, G. C. Sparagna, C. S. Long, et al. Restoration of CREB function is linked to completion and stabilization of adaptive cardiac hypertrophy in response to exercise Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H246 - H259. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. W. Dorn II The Fuzzy Logic of Physiological Cardiac Hypertrophy Hypertension, May 1, 2007; 49(5): 962 - 970. [Full Text] [PDF]
|
|
|
|
 |
|
 B. L.J.H. Kietselaer, C. P.M. Reutelingsperger, H. H. Boersma, G. A.K. Heidendal, I. H. Liem, H. J.G.M. Crijns, J. Narula, and L. Hofstra Noninvasive Detection of Programmed Cell Loss with 99mTc-Labeled Annexin A5 in Heart Failure J. Nucl. Med., April 1, 2007; 48(4): 562 - 567. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Krishnamurthy, V. Subramanian, M. Singh, and K. Singh {beta}1 Integrins Modulate {beta}-Adrenergic Receptor-Stimulated Cardiac Myocyte Apoptosis and Myocardial Remodeling Hypertension, April 1, 2007; 49(4): 865 - 872. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Ashrafian and H. Watkins Reviews of Translational Medicine and Genomics in Cardiovascular Disease: New Disease Taxonomy and Therapeutic Implications: Cardiomyopathies: Therapeutics Based on Molecular Phenotype J. Am. Coll. Cardiol., March 27, 2007; 49(12): 1251 - 1264. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Merkle, S. Frantz, M. P. Schon, J. Bauersachs, M. Buitrago, R. J.A. Frost, E. M. Schmitteckert, M. J. Lohse, and S. Engelhardt A Role for Caspase-1 in Heart Failure Circ. Res., March 16, 2007; 100(5): 645 - 653. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Diwan and G. W. Dorn II Decompensation of Cardiac Hypertrophy: Cellular Mechanisms and Novel Therapeutic Targets Physiology, February 1, 2007; 22(1): 56 - 64. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Hilfiker-Kleiner, U. Landmesser, and H. Drexler Molecular Mechanisms in Heart Failure: Focus on Cardiac Hypertrophy, Inflammation, Angiogenesis, and Apoptosis J. Am. Coll. Cardiol., October 27, 2006; 48(9_Suppl_A): A56 - A66. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. A. Williams, A. Verhovez, A. Milan, F. Veglio, and P. Mulatero Protective Effect of Spironolactone on Endothelial Cell Apoptosis Endocrinology, May 1, 2006; 147(5): 2496 - 2505. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Minhas, R. M. Saraiva, K. H. Schuleri, S. Lehrke, M. Zheng, A. P. Saliaris, C. E. Berry, K. M. Vandegaer, D. Li, and J. M. Hare Xanthine Oxidoreductase Inhibition Causes Reverse Remodeling in Rats With Dilated Cardiomyopathy Circ. Res., February 3, 2006; 98(2): 271 - 279. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Miyamoto, A. L. Howes, J. W. Adams, G. W. Dorn II, and J. H. Brown Ca2+ Dysregulation Induces Mitochondrial Depolarization and Apoptosis: ROLE OF Na+/Ca2+ EXCHANGER AND AKT J. Biol. Chem., November 18, 2005; 280(46): 38505 - 38512. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. B. Morris, B. Kenney, H. Huynh, and E. A. Woodcock Regulation of the Proapoptotic Factor FOXO1 (FKHR) in Cardiomyocytes by Growth Factors and {alpha}1-Adrenergic Agonists Endocrinology, October 1, 2005; 146(10): 4370 - 4376. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. P.M. van Empel, A. T.A. Bertrand, L. Hofstra, H. J. Crijns, P. A. Doevendans, and L. J. De Windt Myocyte apoptosis in heart failure Cardiovasc Res, July 1, 2005; 67(1): 21 - 29. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. M. Syed, H. S. Hahn, A. Odley, Y. Guo, J. G. Vallejo, R. A. Lynch, D. L. Mann, R. Bolli, and G. W. Dorn II Proapoptotic Effects of Caspase-1/Interleukin-Converting Enzyme Dominate in Myocardial Ischemia Circ. Res., May 27, 2005; 96(10): 1103 - 1109. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Tao, J. Kim, S. Faubel, J. C. Wu, S. A. Falk, R. W. Schrier, and C. L. Edelstein Caspase inhibition reduces tubular apoptosis and proliferation and slows disease progression in polycystic kidney disease PNAS, May 10, 2005; 102(19): 6954 - 6959. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-Y. Xiao, M. Chen, Z. Zsengeller, H. Li, L. Kiss, M. Kollai, and C. Szabo Poly(ADP-Ribose) Polymerase Promotes Cardiac Remodeling, Contractile Failure, and Translocation of Apoptosis-Inducing Factor in a Murine Experimental Model of Aortic Banding and Heart Failure J. Pharmacol. Exp. Ther., March 1, 2005; 312(3): 891 - 898. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. T. Crow, K. Mani, Y.-J. Nam, and R. N. Kitsis The Mitochondrial Death Pathway and Cardiac Myocyte Apoptosis Circ. Res., November 12, 2004; 95(10): 957 - 970. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. R. Alcendor, L. A. Kirshenbaum, S.-i. Imai, S. F. Vatner, and J. Sadoshima Silent Information Regulator 2{alpha}, a Longevity Factor and Class III Histone Deacetylase, Is an Essential Endogenous Apoptosis Inhibitor in Cardiac Myocytes Circ. Res., November 12, 2004; 95(10): 971 - 980. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sano and M. D. Schneider Cyclin-Dependent Kinase-9: An RNAPII Kinase at the Nexus of Cardiac Growth and Death Cascades Circ. Res., October 29, 2004; 95(9): 867 - 876. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. L. DeBiasi, B. A. Robinson, B. Sherry, R. Bouchard, R. D. Brown, M. Rizeq, C. Long, and K. L. Tyler Caspase Inhibition Protects against Reovirus-Induced Myocardial Injury In Vitro and In Vivo J. Virol., October 15, 2004; 78(20): 11040 - 11050. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. R. Pitts and C. F. Toombs Coverslip hypoxia: a novel method for studying cardiac myocyte hypoxia and ischemia in vitro Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1801 - H1812. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. von Harsdorf "Fas-ten" Your Seat Belt: Anti-apoptotic Treatment in Heart Failure Takes Off Circ. Res., September 17, 2004; 95(6): 554 - 556. [Full Text] [PDF]
|
|
|
|
|
|
V. P.M van Empel and L. J De Windt Myocyte hypertrophy and apoptosis: a balancing act Cardiovasc Res, August 15, 2004; 63(3): 487 - 499. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Zhang, S. Miyamoto, and J. H. Brown Cardiomyocyte Calcium and Calcium/Calmodulin-dependent Protein Kinase II: Friends or Foes? Recent Prog. Horm. Res., January 1, 2004; 59(1): 141 - 168. [Abstract] [Full Text]
|
|
|
|
|
|
K. A. Webster and N. H. Bishopric Apoptosis Inhibitors for Heart Disease Circulation, December 16, 2003; 108(24): 2954 - 2956. [Full Text] [PDF]
|
|