Cofilin-2 phosphorylation and sequestration in myocardial aggregates: Novel pathogenetic mechanisms for idiopathic dilated cardiomyopathy

Khaushik Subramanian, Davide Gianni, Cristina Balla, Gabriele Egidy Assenza, Mugdha Joshi, Marc J. Semigran, Thomas E. Macgillivray, Jennifer E. Van Eyk, Giulio Agnetti, Nazareno Paolocci, James R. Bamburg, Pankaj B. Agrawal, Federica Del Monte

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Background Recently, tangles and plaque-like aggregates have been identified in certain cases of dilated cardiomyopathy (DCM). This suggests a potential underlying cause for the one-third of cases, traditionally labeled idiopathic (iDCM), where there is no specific diagnostic test or targeted therapy. Objectives 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.

Original languageEnglish (US)
Pages (from-to)1199-1214
Number of pages16
JournalJournal of the American College of Cardiology
Volume65
Issue number12
DOIs
StatePublished - Mar 31 2015

Keywords

  • adenovirus
  • heart failure
  • nemaline

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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