Reduced Cx43 expression triggers increased fibrosis due to enhanced fibroblast activity.
SourceCirculation-Arrhythmia and Electrophysiology, 5, 2, (2012), pp. 380-390
1 april 2012
Article / Letter to editor
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Circulation-Arrhythmia and Electrophysiology
SubjectIGMD 3: Genomic disorders and inherited multi-system disorders
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. METHODS AND 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 1alpha2 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.
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