Consequences of unlocking the cardiac myosin molecule in human myocarditis and cardiomyopathies

Adita Mascaro-Blanco, Kathy Alvarez, Xichun Yu, JoAnn Lindenfeld, Leann Olansky, Timothy Lyons, David Duvall, Janet S. Heuser, Albina Gosmanova, Carl J. Rubenstein, Leslie T Jr. Cooper, David C. Kem, Madeleine W. Cunningham

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Myocarditis, often initiated by viral infection, may progress to autoimmune inflammatory heart disease, dilated cardiomyopathy and heart failure. Although cardiac myosin is a dominant autoantigen in animal models of myocarditis and is released from the heart during viral myocarditis, the characterization, role and significance of anti-cardiac myosin autoantibodies is poorly defined. In our study, we define the human cardiac myosin epitopes in human myocarditis and cardiomyopathies and establish a mechanism to explain how anti-cardiac myosin autoantibodies may contribute to heart disease. We show that autoantibodies to cardiac myosin in sera from myocarditis and dilated cardiomyopathies in humans targeted primarily epitopes in the S2 hinge region of cardiac myosin. In addition, anti-cardiac myosin antibodies in sera or purified IgG from myocarditis and cardiomyopathy targeted the beta-adrenergic receptor and induced antibody-mediated cAMP-dependent protein kinase A (PKA) cell signaling activity in heart cells. Antibody-mediated PKA activity in sera was abrogated by absorption with anti-human IgG. Antibody-mediated cell signaling of PKA was blocked by antigen-specific inhibition by human cardiac myosin or the beta-adrenergic receptor but not the alpha adrenergic receptor or bovine serum albumin. Propranolol, a beta blocker and inhibitor of the beta-adrenergic receptor pathway also blocked the antibody-mediated signaling of the beta-adrenergic receptor and PKA. The data suggest that IgG antibody against human cardiac myosin reacts with the beta-adrenergic receptor and triggers PKA signaling in heart cells. In summary, we have identified a new class of crossreactive autoantibodies against human cardiac myosin and the beta-adrenergic receptor in the heart. In addition, we have defined disease specific peptide epitopes in the human cardiac myosin rod S2 region in human myocarditis and cardiomyopathy as well as a mechanistic role of autoantibody in the pathogenesis of disease.

Original languageEnglish (US)
Pages (from-to)442-453
Number of pages12
JournalAutoimmunity
Volume41
Issue number6
DOIs
StatePublished - 2008

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Cardiac Myosins
Myocarditis
Cardiomyopathies
Cyclic AMP-Dependent Protein Kinases
Receptors, Adrenergic, beta
Autoantibodies
Antibodies
Epitopes
Dilated Cardiomyopathy
Heart Diseases
beta-Adrenergic Receptor Kinases
Immunoglobulin G
Serum
Myosin Subfragments
Receptors, Adrenergic, alpha
Autoantigens
Virus Diseases
Bovine Serum Albumin
Propranolol
Animal Models

Keywords

  • Autoimmunity
  • Beta-adrenergic receptor
  • Cardiomyopathy
  • Myocarditis
  • Myosin

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Mascaro-Blanco, A., Alvarez, K., Yu, X., Lindenfeld, J., Olansky, L., Lyons, T., ... Cunningham, M. W. (2008). Consequences of unlocking the cardiac myosin molecule in human myocarditis and cardiomyopathies. Autoimmunity, 41(6), 442-453. https://doi.org/10.1080/08916930802031579

Consequences of unlocking the cardiac myosin molecule in human myocarditis and cardiomyopathies. / Mascaro-Blanco, Adita; Alvarez, Kathy; Yu, Xichun; Lindenfeld, JoAnn; Olansky, Leann; Lyons, Timothy; Duvall, David; Heuser, Janet S.; Gosmanova, Albina; Rubenstein, Carl J.; Cooper, Leslie T Jr.; Kem, David C.; Cunningham, Madeleine W.

In: Autoimmunity, Vol. 41, No. 6, 2008, p. 442-453.

Research output: Contribution to journalArticle

Mascaro-Blanco, A, Alvarez, K, Yu, X, Lindenfeld, J, Olansky, L, Lyons, T, Duvall, D, Heuser, JS, Gosmanova, A, Rubenstein, CJ, Cooper, LTJ, Kem, DC & Cunningham, MW 2008, 'Consequences of unlocking the cardiac myosin molecule in human myocarditis and cardiomyopathies', Autoimmunity, vol. 41, no. 6, pp. 442-453. https://doi.org/10.1080/08916930802031579
Mascaro-Blanco A, Alvarez K, Yu X, Lindenfeld J, Olansky L, Lyons T et al. Consequences of unlocking the cardiac myosin molecule in human myocarditis and cardiomyopathies. Autoimmunity. 2008;41(6):442-453. https://doi.org/10.1080/08916930802031579
Mascaro-Blanco, Adita ; Alvarez, Kathy ; Yu, Xichun ; Lindenfeld, JoAnn ; Olansky, Leann ; Lyons, Timothy ; Duvall, David ; Heuser, Janet S. ; Gosmanova, Albina ; Rubenstein, Carl J. ; Cooper, Leslie T Jr. ; Kem, David C. ; Cunningham, Madeleine W. / Consequences of unlocking the cardiac myosin molecule in human myocarditis and cardiomyopathies. In: Autoimmunity. 2008 ; Vol. 41, No. 6. pp. 442-453.
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