Khaushik Subramanian1, Davide Gianni1, Cristina Balla2, Gabriele Egidy Assenza3, Mugdha Joshi4, Marc J Semigran5, Thomas E Macgillivray6, Jennifer E Van Eyk7, Giulio Agnetti8, Nazareno Paolocci9, James R Bamburg10, Pankaj B Agrawal4, Federica Del Monte11. 1. Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts. 2. Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Division of Cardiology, Sapienza University, Rome, Italy. 3. Division of Cardiology, Sapienza University, Rome, Italy. 4. Divisions of Newborn Medicine and Genetics and Program in Genomics, Children's Hospital, Boston, Massachusetts. 5. Heart Center, Massachusetts General Hospital, Boston, Massachusetts. 6. Cardiovascular Surgery, Massachusetts General Hospital, Boston, Massachusetts. 7. National Heart Lung Blood Institute Proteomics Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. 8. 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. 9. Heart and Vascular Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland. 10. Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado. 11. Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Heart Center, Massachusetts General Hospital, Boston, Massachusetts. Electronic address: fdelmont@bidmc.harvard.edu.
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] 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.
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] 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.
Authors: Davide Gianni; Airong Li; Giuseppina Tesco; Kenneth M McKay; John Moore; Kunal Raygor; Marcello Rota; Judith K Gwathmey; G William Dec; Thomas Aretz; Annarosa Leri; Marc J Semigran; Piero Anversa; Thomas E Macgillivray; Rudolph E Tanzi; Federica del Monte Journal: Circulation Date: 2010-03-01 Impact factor: 29.690
Authors: Pankaj B Agrawal; Rebecca S Greenleaf; Kinga K Tomczak; Vilma-Lotta Lehtokari; Carina Wallgren-Pettersson; William Wallefeld; Nigel G Laing; Basil T Darras; Sutherland K Maciver; Philip R Dormitzer; Alan H Beggs Journal: Am J Hum Genet Date: 2006-11-14 Impact factor: 11.025
Authors: Megan T Quintana; Traci L Parry; Jun He; Cecelia C Yates; Tatiana N Sidorova; Katherine T Murray; James R Bain; Christopher B Newgard; Michael J Muehlbauer; Samuel C Eaton; Akinori Hishiya; Shin Takayama; Monte S Willis Journal: Am J Pathol Date: 2016-06-17 Impact factor: 4.307
Authors: Luca Troncone; Marco Luciani; Matthew Coggins; Elissa H Wilker; Cheng-Ying Ho; Kari Elise Codispoti; Matthew P Frosch; Rakez Kayed; Federica Del Monte Journal: J Am Coll Cardiol Date: 2016-12-06 Impact factor: 24.094