title: Cofilin-2 phosphorylation and sequestration in myocardial aggregates: novel pathogenetic mechanisms for idiopathic dilated cardiomyopathy.
abstract: BACKGROUND
  Recently, tangles and plaque-like aggregates have been identified in certain cases of dilated cardiomyopathy (DCM), traditionally labeled idiopathic (iDCM), where there is no specific diagnostic test or targeted therapy. This suggests a potential underlying cause for some of the iDCM cases. [Corrected]
  
  
  OBJECTIVE
  This study sought to identify the make-up of myocardial aggregates to understand the molecular mechanisms of these cases of DCM; this strategy has been central to understanding Alzheimer's disease.
  
  
  METHODS
  Aggregates were extracted from human iDCM samples with high congophilic reactivity (an indication of plaque presence), and the findings were validated in a larger cohort of samples. We tested the expression, distribution, and activity of cofilin in human tissue and generated a cardiac-specific knockout mouse model to investigate the functional impact of the human findings. We also modeled cofilin inactivity in vitro by using pharmacological and genetic gain- and loss-of-function approaches.
  
  
  RESULTS
  Aggregates in human myocardium were enriched for cofilin-2, an actin-depolymerizing protein known to participate in neurodegenerative diseases and nemaline myopathy. Cofilin-2 was predominantly phosphorylated, rendering it inactive. Cardiac-specific haploinsufficiency of cofilin-2 in mice recapitulated the human disease's morphological, functional, and structural phenotype. Pharmacological stimulation of cofilin-2 phosphorylation and genetic overexpression of the phosphomimetic protein promoted the accumulation of "stress-like" fibers and severely impaired cardiomyocyte contractility.
  
  
  CONCLUSIONS
  Our study provides the first biochemical characterization of prefibrillar myocardial aggregates in humans and the first report to link cofilin-2 to cardiomyopathy. The findings suggest a common pathogenetic mechanism connecting certain iDCMs and other chronic degenerative diseases, laying the groundwork for new therapeutic strategies.
authors: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors: Khaushik
authors: K
authors: Subramanian
authors: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors: Davide
authors: D
authors: Gianni
authors: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Division of Cardiology, Sapienza University, Rome, Italy.
authors: Cristina
authors: C
authors: Balla
authors: Division of Cardiology, Sapienza University, Rome, Italy.
authors: Gabriele Egidy
authors: GE
authors: Assenza
authors: Divisions of Newborn Medicine and Genetics and Program in Genomics, Children's Hospital, Boston, Massachusetts.
authors: Mugdha
authors: M
authors: Joshi
authors: Heart Center, Massachusetts General Hospital, Boston, Massachusetts.
authors: Marc J
authors: MJ
authors: Semigran
authors: Cardiovascular Surgery, Massachusetts General Hospital, Boston, Massachusetts.
authors: Thomas E
authors: TE
authors: Macgillivray
authors: National Heart Lung Blood Institute Proteomics Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Jennifer E
authors: JE
authors: Van Eyk
authors: National Heart Lung Blood Institute Proteomics Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.
authors: Giulio
authors: G
authors: Agnetti
authors: Heart and Vascular Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Nazareno
authors: N
authors: Paolocci
authors: Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado.
authors: James R
authors: JR
authors: Bamburg
authors: Divisions of Newborn Medicine and Genetics and Program in Genomics, Children's Hospital, Boston, Massachusetts.
authors: Pankaj B
authors: PB
authors: Agrawal
authors: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Heart Center, Massachusetts General Hospital, Boston, Massachusetts. Electronic address: fdelmont@bidmc.harvard.edu.
authors: Federica
authors: F
authors: Del Monte
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000503:physiopathology* / Q000601:surgery; D051340:Cofilin 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005629:Frozen Sections; D005786:Gene Expression Regulation; D016027:Heart Transplantation; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009206:Myocardium / Q000166:cytology; D010766:Phosphorylation / Q000235:genetics / Q000502:physiology; D012494:Sampling Studies; D012680:Sensitivity and Specificity
chemical_list: D051340:Cofilin 2
keywords: adenovirus; heart failure; nemaline