title: Apoptosis repressor with caspase recruitment domain is required for cardioprotection in response to biomechanical and ischemic stress.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Cardiology, Campus Virchow Clinic, Charité, Humboldt University, HELIOS GmbH, Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Donath
authors.forename: Peifeng
authors.initials: P
authors.lastname: Li
authors.forename: Christian
authors.initials: C
authors.lastname: Willenbockel
authors.forename: Nidal
authors.initials: N
authors.lastname: Al-Saadi
authors.forename: Volkmar
authors.initials: V
authors.lastname: Gross
authors.forename: Thomas
authors.initials: T
authors.lastname: Willnow
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.forename: Ulrich
authors.initials: U
authors.lastname: Martin
authors.forename: Johann
authors.initials: J
authors.lastname: Bauersachs
authors.forename: Kai C
authors.initials: KC
authors.lastname: Wollert
authors.forename: Rainer
authors.initials: R
authors.lastname: Dietz
authors.forename: Rüdiger
authors.initials: R
authors.lastname: von Harsdorf
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000032:analysis / Q000172:deficiency / Q000502:physiology*; D001696:Biomechanical Phenomena; D001794:Blood Pressure; D015536:Down-Regulation; D005355:Fibrosis; D006333:Heart Failure / Q000209:etiology* / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000032:analysis / Q000172:deficiency / Q000502:physiology*; D009203:Myocardial Infarction / Q000209:etiology; D017202:Myocardial Ischemia; D013312:Stress, Physiological
chemical_list: D051017:Apoptosis Regulatory Proteins; D009124:Muscle Proteins; C491787:Nol3 protein, mouse