Calreticulin overexpression correlates with integrin-α5 and transforming growth factor-β1 expression in the atria of patients with rheumatic valvular disease and atrial fibrillation

Int J Cardiol. 2013 Oct 3;168(3):2177-85. doi: 10.1016/j.ijcard.2013.01.239. Epub 2013 Mar 7.

Abstract

Objectives: The aim of this study was to determine whether altered calreticulin expression and distribution contribute to the pathogenesis of atrial fibrillation (AF) associated with valvular heart disease (VHD).

Background: AF affects electrophysiological and structural changes that exacerbate AF. Atrial remodeling reportedly underlies AF generation, but the precise mechanism of atrial remodeling in AF remains unclear.

Methods: Right and left atrial specimens were obtained from 68 patients undergoing valve replacement surgery. The patients were divided into sinus rhythm (SR; n=25), paroxysmal AF (PaAF; n=11), and persistent AF (PeAF; AF lasting >6 months; n=32) groups. Calreticulin, integrin-α5, and transforming growth factor-β1 (TGF-β1) mRNA and protein expression were measured. We also performed immunoprecipitation for calreticulin with either calcineurin B or integrin-α5.

Results: Calreticulin, integrin-α5, and TGF-β1 mRNA and protein expression were increased in the AF groups, especially in the left atrium in patients with mitral valve disease. Calreticulin interacted with both calcineurin B and integrin-α5. Integrin-α5 expression correlated with TGF-β1 expression, while calreticulin expression correlated with integrin-α5 and TGF-β1 expression. Despite similar cardiac function classifications, calreticulin expression was greater in the PeAF group than in the SR group.

Conclusions: Calreticulin, integrin-α5, and TGF-β1 expression was increased in atrial tissue in patients with AF and was related to AF type, suggesting that calreticulin is involved in the pathogenesis of AF in VHD patients.

Keywords: AF; Atrial fibrillation; Atrial fibrosis; CHD; Calreticulin; DVD; Human myocardium; Integrin-α5; MVD; PaAF; PeAF; SR; Transforming growth factor-β1; VHD; atrial fibrillation; congenital heart disease; double valvular disease (mitral and aortic valves); mitral valvular disease; paroxysmal atrial fibrillation; persistent atrial fibrillation; sinus rhythm; valvular heart disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Atrial Fibrillation / etiology
  • Atrial Fibrillation / genetics*
  • Atrial Fibrillation / metabolism
  • Blotting, Western
  • Calreticulin / biosynthesis
  • Calreticulin / genetics*
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation*
  • Heart Atria / metabolism*
  • Heart Atria / pathology
  • Heart Valve Diseases / complications
  • Heart Valve Diseases / genetics*
  • Heart Valve Diseases / metabolism
  • Humans
  • Immunohistochemistry
  • Immunoprecipitation
  • Integrin alpha5 / biosynthesis
  • Integrin alpha5 / genetics*
  • Male
  • Middle Aged
  • RNA, Messenger / metabolism
  • Retrospective Studies
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rheumatic Heart Disease / complications
  • Rheumatic Heart Disease / metabolism
  • Transforming Growth Factor beta1 / biosynthesis
  • Transforming Growth Factor beta1 / genetics*
  • Young Adult

Substances

  • Calreticulin
  • Integrin alpha5
  • RNA, Messenger
  • Transforming Growth Factor beta1