Published Online
on February 27, 2006

A more recent version of this article appeared on March 7, 2006

This Article Full Text (PDF) All Versions of this Article: 113/9/1203    most recent CIRCULATIONAHA.105.576785v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Donath, S. Search for Related Content PubMed PubMed Citation Articles by Donath, S. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Protein UniGene Medline Plus Health Information Heart Failure Related Collections Other myocardial biology Congestive Animal models of human disease Apoptosis Acute myocardial infarction

Submitted on July 19, 2005
Revised on December 3, 2005
Accepted on December 21, 2005

Apoptosis Repressor With Caspase Recruitment Domain Is Required for Cardioprotection in Response to Biomechanical and Ischemic Stress

Stefan Donath MD, Peifeng Li PhD, Christian Willenbockel DVM, Nidal Al-Saadi MD, Volkmar Gross PhD, Thomas Willnow PhD, Michael Bader PhD, Ulrich Martin MD, Johann Bauersachs MD, Kai C. Wollert MD, Rainer Dietz MD, Rüdiger von Harsdorf MD^*, on behalf of the German Heart Failure Network

From the Departments of Cardiology, Campus Virchow Clinic, Charité, Humboldt University, and Franz-Volhard Clinic, HELIOS GmbH, Berlin, Germany (S.D., P.L., N.A., R.D., R.v.H.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (S.D., V.G., T.W., M.B., R.v.H.); Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany (C.W., K.C.W.); Leibniz Research Laboratories for Biotechnology and Artificial Organs, Department of Thoracic and Cardiovascular Surgery, Hannover Medical School, Hannover, Germany (U.M.); and Department of Internal Medicine I, Julius-Maximilians University, Würzburg, Germany (J.B.).

^* To whom correspondence should be addressed. E-mail: rudiger.vonharsdorf{at}uhn.on.ca.

Background--Ischemic heart disease and heart failure are associated with an increased loss of cardiomyocytes due to apoptosis. Whether cardiomyocyte apoptosis plays a causal role in the pathogenesis of heart failure remains enigmatic. The apoptosis repressor with caspase recruitment domain (ARC) is a recently discovered antiapoptotic factor with a highly specific expression pattern in striated muscle and neurons. ARC is a master regulator of cardiac death signaling because it is the only known factor that specifically inhibits both the intrinsic and extrinsic apoptotic death pathway. In this study we attempted to elucidate the physiological role of ARC and to understand pathophysiological consequences resulting from its deletion.

Methods and Results--We generated ARC-deficient mice, which developed normally to adulthood and had no abnormality in cardiac morphology and function under resting conditions. On biomechanical stress induced by aortic banding, ARC-deficient mice developed accelerated cardiomyopathy compared with littermate controls, which was characterized by reduced contractile function, cardiac enlargement, and myocardial fibrosis. Likewise, ischemia/reperfusion injury of ARC-deficient mice resulted in markedly increased myocardial infarct sizes. Although in both instances a significant increase in apoptotic cardiomyocytes could be observed in ARC-deficient mice, neither in vitro nor in vivo studies revealed any effect of ARC on classic hypertrophic cardiomyocyte growth responses. The pathophysiological relevance of downregulated ARC levels was underscored by specimens from failing human hearts showing markedly reduced ARC protein levels.

Conclusions--Our study identifies a tissue-specific antiapoptotic factor that is downregulated in human failing myocardium and that is required for cardioprotection in pressure overload and ischemia.

Key words: apoptosis • heart failure • hypertrophy • ischemia • myocardial infarction

This article has been cited by other articles:

				X. Yu and D. C. Kem Proteasome inhibition during myocardial infarction Cardiovasc Res, December 4, 2009; (2009) cvp309v3. [Abstract] [Full Text] [PDF]

				N. Defer, J. Wan, R. Souktani, B. Escoubet, M. Perier, P. Caramelle, S. Manin, V. Deveaux, M.-C. Bourin, A. Zimmer, et al. The cannabinoid receptor type 2 promotes cardiac myocyte and fibroblast survival and protects against ischemia/reperfusion-induced cardiomyopathy FASEB J, July 1, 2009; 23(7): 2120 - 2130. [Abstract] [Full Text] [PDF]

				R. L Kao, W. Browder, and C. Li Cellular Cardiomyoplasty: What Have We Learned? Asian Cardiovasc Thorac Ann, January 1, 2009; 17(1): 89 - 101. [Abstract] [Full Text] [PDF]

				G. A. MacGowan Good news for mice with heart attacks: preventing acute myocardial injury by inhibiting apoptosis Cardiovasc Res, January 1, 2009; 81(1): 1 - 2. [Full Text] [PDF]

				C. C. Chua, J. Gao, Y.-S. Ho, X. Xu, I-C. Kuo, K.-Y. Chua, H. Wang, R. C. Hamdy, J. C. Reed, and B. H.L. Chua Over-expression of a modified bifunctional apoptosis regulator protects against cardiac injury and doxorubicin-induced cardiotoxicity in transgenic mice Cardiovasc Res, January 1, 2009; 81(1): 20 - 27. [Abstract] [Full Text] [PDF]

				D. Westermann, A. Riad, O. Lettau, A. Roks, K. Savvatis, P. M. Becher, F. Escher, A.H. Jan Danser, H.-P. Schultheiss, and C. Tschope Renin Inhibition Improves Cardiac Function and Remodeling After Myocardial Infarction Independent of Blood Pressure Hypertension, December 1, 2008; 52(6): 1068 - 1075. [Abstract] [Full Text] [PDF]

				J.-O. Pyo, J. Nah, H.-J. Kim, J.-W. Chang, Y.-W. Song, D.-K. Yang, D.-G. Jo, H.-R. Kim, H.-J. Chae, S.-W. Chae, et al. Protection of Cardiomyocytes from Ischemic/Hypoxic Cell Death via Drbp1 and pMe2GlyDH in Cardio-specific ARC Transgenic Mice J. Biol. Chem., November 7, 2008; 283(45): 30707 - 30714. [Abstract] [Full Text] [PDF]

				N. C. Moss, R.-H. Tang, M. Willis, W. E. Stansfield, A. S. Baldwin, and C. H. Selzman Inhibitory kappa B kinase-beta is a target for specific nuclear factor kappa B-mediated delayed cardioprotection. J. Thorac. Cardiovasc. Surg., November 1, 2008; 136(5): 1274 - 1279. [Abstract] [Full Text] [PDF]

				I. Murtaza, H.-X. Wang, X. Feng, N. Alenina, M. Bader, B. S. Prabhakar, and P.-F. Li Down-regulation of Catalase and Oxidative Modification of Protein Kinase CK2 Lead to the Failure of Apoptosis Repressor with Caspase Recruitment Domain to Inhibit Cardiomyocyte Hypertrophy J. Biol. Chem., March 7, 2008; 283(10): 5996 - 6004. [Abstract] [Full Text] [PDF]

				L. H. Chen, C. C. Jiang, R. Watts, R. F. Thorne, K. A. Kiejda, X. D. Zhang, and P. Hersey Inhibition of Endoplasmic Reticulum Stress-Induced Apoptosis of Melanoma Cells by the ARC Protein Cancer Res., February 1, 2008; 68(3): 834 - 842. [Abstract] [Full Text] [PDF]

				D. Sanchis, M. Llovera, M. Ballester, and J. X. Comella An alternative view of apoptosis in heart development and disease Cardiovasc Res, February 1, 2008; 77(3): 448 - 451. [Full Text] [PDF]

				P. A. da Costa Martins and L. J. De Windt Nix: The Cardiac Styx Between Life and Death Circulation, January 22, 2008; 117(3): 338 - 340. [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]

				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]