title: Reduced Cx43 expression triggers increased fibrosis due to enhanced fibroblast activity.
abstract: BACKGROUND
  Arrhythmogenic ventricular remodeling is hallmarked by both reduced gap junction expression and increased collagen deposition. We hypothesized that reduced connexin43 (Cx43) expression is responsible for enhanced fibrosis in the remodeled heart, resulting in an arrhythmogenic substrate. Therefore, we investigated the effect of normal or reduced Cx43 expression on the formation of fibrosis in a physiological (aging) and pathophysiological (transverse aortic constriction [TAC]) mouse model.
  
  
  RESULTS
  The Cx43(fl/fl) and Cx43(CreER(T)/fl) mice were aged 18 to 21 months or, at the age of 3 months, either TAC or sham operated and euthanized after 16 weeks. Epicardial activation mapping of the right and left ventricles was performed on Langendorff perfused hearts. Sustained ventricular arrhythmias were induced in 0 of 11 aged Cx43(fl/fl) and 10 of 15 Cx43(Cre-ER(T)/fl) mice (P<0.01). Cx43 expression was reduced by half in aged Cx43(CreER(T)/fl) compared with aged Cx43(fl/fl) mice, whereas collagen deposition was significantly increased from 1.1±0.2% to 7.4±1.3%. Aged Cx43(CreER(T)/fl) mice with arrhythmias had significantly higher levels of fibrosis and conduction heterogeneity than aged Cx43(CreER(T)/fl) mice without arrhythmias. The TAC operation significantly increased fibrosis in control compared with sham (4.0±1.2% versus 0.4±0.06%), but this increase was significantly higher in Cx43(CreER(T)/fl) mice (10.8±1.4%). Discoidin domain receptor 2 expression was unchanged, but procollagen peptide I and III expression and collagen type 1α2 mRNA levels were higher in TAC-operated Cx43HZ mice.
  
  
  CONCLUSIONS
  Reduced cellular coupling results in more excessive collagen deposition during aging or pressure overload in mice due to enhanced fibroblast activity, leading to increased conduction in homogeneity and proarrhythmia.
authors.affiliation: Division of Heart and Lungs, Department of Medical Physiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: John A
authors.initials: JA
authors.lastname: Jansen
authors.forename: Toon A B
authors.initials: TA
authors.lastname: van Veen
authors.forename: Sanne
authors.initials: S
authors.lastname: de Jong
authors.forename: Roel
authors.initials: R
authors.lastname: van der Nagel
authors.forename: Leonie
authors.initials: L
authors.lastname: van Stuijvenberg
authors.forename: Helen
authors.initials: H
authors.lastname: Driessen
authors.forename: Ronald
authors.initials: R
authors.lastname: Labzowski
authors.forename: Carolin M
authors.initials: CM
authors.lastname: Oefner
authors.forename: Astrid A
authors.initials: AA
authors.lastname: Bosch
authors.forename: Tri Q
authors.initials: TQ
authors.lastname: Nguyen
authors.forename: Roel
authors.initials: R
authors.lastname: Goldschmeding
authors.forename: Marc A
authors.initials: MA
authors.lastname: Vos
authors.forename: Jacques M T
authors.initials: JM
authors.lastname: de Bakker
authors.forename: Harold V M
authors.initials: HV
authors.lastname: van Rijen
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000503:physiopathology*; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000503:physiopathology; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D018031:Connexin 43 / Q000172:deficiency*; D003251:Constriction, Pathologic / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000473:pathology*; D005355:Fibrosis; D006329:Heart Conduction System / Q000503:physiopathology; D008297:Male; D051379:Mice; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D013312:Stress, Physiological / Q000502:physiology
chemical_list: D018031:Connexin 43; C543076:GJA1 protein, mouse; D003094:Collagen