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: Research - peer-reviewArticle

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.

LanguageEnglish (US)
Pages1199-1214
Number of pages16
JournalJournal of the American College of Cardiology
Volume65
Issue number12
DOIs
StatePublished - Mar 31 2015

Fingerprint

Cofilin 2
Dilated Cardiomyopathy
Phosphorylation
Actin Depolymerizing Factors
Pharmacology
Therapeutics
Nemaline Myopathies
Haploinsufficiency
Stress Fibers
Cardiomyopathies
Routine Diagnostic Tests
Cardiac Myocytes
Knockout Mice
Neurodegenerative Diseases
Myocardium
Alzheimer Disease
Chronic Disease
Phenotype
Proteins
In Vitro Techniques

Keywords

  • adenovirus
  • heart failure
  • nemaline

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Cofilin-2 phosphorylation and sequestration in myocardial aggregates : Novel pathogenetic mechanisms for idiopathic dilated cardiomyopathy. / Subramanian, Khaushik; Gianni, Davide; Balla, Cristina; Assenza, Gabriele Egidy; Joshi, Mugdha; Semigran, Marc J.; Macgillivray, Thomas E.; Van Eyk, Jennifer E.; Agnetti, Giulio; Paolocci, Nazareno; Bamburg, James R.; Agrawal, Pankaj B.; Del Monte, Federica.

In: Journal of the American College of Cardiology, Vol. 65, No. 12, 31.03.2015, p. 1199-1214.

Research output: Research - peer-reviewArticle

Subramanian, K, Gianni, D, Balla, C, Assenza, GE, Joshi, M, Semigran, MJ, Macgillivray, TE, Van Eyk, JE, Agnetti, G, Paolocci, N, Bamburg, JR, Agrawal, PB & Del Monte, F 2015, 'Cofilin-2 phosphorylation and sequestration in myocardial aggregates: Novel pathogenetic mechanisms for idiopathic dilated cardiomyopathy' Journal of the American College of Cardiology, vol 65, no. 12, pp. 1199-1214. DOI: 10.1016/j.jacc.2015.01.031
Subramanian, Khaushik ; Gianni, Davide ; Balla, Cristina ; Assenza, Gabriele Egidy ; Joshi, Mugdha ; Semigran, Marc J. ; Macgillivray, Thomas E. ; Van Eyk, Jennifer E. ; Agnetti, Giulio ; Paolocci, Nazareno ; Bamburg, James R. ; Agrawal, Pankaj B. ; Del Monte, Federica. / Cofilin-2 phosphorylation and sequestration in myocardial aggregates : Novel pathogenetic mechanisms for idiopathic dilated cardiomyopathy. In: Journal of the American College of Cardiology. 2015 ; Vol. 65, No. 12. pp. 1199-1214
@article{46441eb2c1904633b0e65ca1f1411f49,
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). 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.",
keywords = "adenovirus, heart failure, nemaline",
author = "Khaushik Subramanian and Davide Gianni and Cristina Balla and Assenza, {Gabriele Egidy} and Mugdha Joshi and Semigran, {Marc J.} and Macgillivray, {Thomas E.} and {Van Eyk}, {Jennifer E.} and Giulio Agnetti and Nazareno Paolocci and Bamburg, {James R.} and Agrawal, {Pankaj B.} and {Del Monte}, Federica",
year = "2015",
month = "3",
doi = "10.1016/j.jacc.2015.01.031",
volume = "65",
pages = "1199--1214",
journal = "Journal of the American College of Cardiology",
issn = "0735-1097",
publisher = "Elsevier USA",
number = "12",

}

TY - JOUR

T1 - Cofilin-2 phosphorylation and sequestration in myocardial aggregates

T2 - Journal of the American College of Cardiology

AU - Subramanian,Khaushik

AU - Gianni,Davide

AU - Balla,Cristina

AU - Assenza,Gabriele Egidy

AU - Joshi,Mugdha

AU - Semigran,Marc J.

AU - Macgillivray,Thomas E.

AU - Van Eyk,Jennifer E.

AU - Agnetti,Giulio

AU - Paolocci,Nazareno

AU - Bamburg,James R.

AU - Agrawal,Pankaj B.

AU - Del Monte,Federica

PY - 2015/3/31

Y1 - 2015/3/31

N2 - 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.

AB - 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.

KW - adenovirus

KW - heart failure

KW - nemaline

UR - http://www.scopus.com/inward/record.url?scp=84925358628&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84925358628&partnerID=8YFLogxK

U2 - 10.1016/j.jacc.2015.01.031

DO - 10.1016/j.jacc.2015.01.031

M3 - Article

VL - 65

SP - 1199

EP - 1214

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

SN - 0735-1097

IS - 12

ER -