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. Methods and Results-The Cx43fl/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 Cx43Cre-ER(T)/fl mice (PϽ0.01). 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 1.1Ϯ0.2% to 7.4Ϯ1.3%. Aged Cx43CreER(T)/fl mice with arrhythmias had significantly higher levels of fibrosis and conduction heterogeneity than aged Cx43CreER(T)/fl mice without arrhythmias. The TAC operation significantly increased fibrosis in control compared with sham (4.0Ϯ1.2% versus 0.4Ϯ0.06%), but this increase was significantly higher in Cx43CreER(T)/fl mice (10.8Ϯ1.4%). Discoidin domain receptor 2 expression was unchanged, but procollagen peptide I and III expression and collagen type 1␣2 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. (Circ Arrhythm Electrophysiol. 2012;5:380-390.)Key Words: arrhythmia Ⅲ collagen Ⅲ electrophysiology mapping Ⅲ connexin43 Ⅲ fibroblast I n the heart, the highly orchestrated propagation of the electric impulse balances on the delicate interplay between excitability, cell-to-cell coupling, and architecture of myocardial tissue. An important aspect of the myocardial architecture is interstitial collagen (fibrosis), which, together with connexin43 (Cx43), determines cell-to-cell coupling in ventricular myocardium. Under normal physiological conditions, the amount of collagen between the cardiomyocytes is low (Ͻ1% of total tissue volume) but contributes to the structural organization of the heart and the anisotropic character of impulse propagation. We recently showed that, in senescent mouse hearts, collagen content was increased (200%) and Cx43 expression was decreased (50%), changes that were associated with increased inducibility of ventricular tachycardias. 1 On the other hand, when the excessive deposition of fibrosis was prevented through long-term inhibition of the renin-angiotensin-aldosterone system, the normal pattern of Cx43 expression was preserved and arrhythmia vulnerability was strongly red...

Functional Characterization of a Novel Truncating Mutation in Lamin A/C Gene in a Family with a Severe Cardiomyopathy with Conduction Defects

“…Moreover, it is conceivable that the down regulation of CX43 in cells expressing D243Gfs*4 may be involved also in the fibrosis found in the index patient. Interestingly, it has been demonstrated that the reduced Cx43 expression in a CX43 transgenic mouse model, triggers increased myocardial fibrosis due to enhanced activity of non-excitable cardiac fibroblasts [37]. Of note, this work suggests that early normalization of Cx43 expression might prevent fibrosis formation and reduce the susceptibility to fatal arrhythmia, underlying the clinical importance in identifying CX43 as the player involved in the cardiomyopathy pathogenesis.…”

Three-Dimensional Impulse Propagation in Myocardium

“…102 In these studies, CVs and activation delays were estimated using high-resolution extracellular epicardial mapping; axial CV was unchanged, whereas significant rate-dependent transverse activation delays were seen. The probability of inducing VT and fibrillation in these hearts was increased by the presence of patchy fibrosis.…”

“…The probability of inducing VT and fibrillation in these hearts was increased by the presence of patchy fibrosis. 96,102 Furthermore, inhibition of the renin-angiotensin-aldosterone system in aging mice limited age-related fibrosis, decreased the extent of electric anisotropy, and lowered arrhythmogeneity. 103 The preservation of axial CV in HF suggests that gap junction remodeling and fibroblast/myofibroblast infiltration have relatively little impact on this parameter.…”

Myocardial connexin-43 and PKC signalling are involved in adaptation of the heart to irradiation-induced injury: Implication of miR-1 and miR-21

“…These myocardial alterations compromise cell-to-cell contacts and Cx43 channels mediated communication in diseased or aged heart and promote the occurrence of malignant arrhythmias (Tribulova et al 2008;Jansen et al 2012;Radosinska et al 2013). Fibrotic remodelling is attributed to miR-21 that is specifically enriched in cardiac fibroblasts promoting their activation and induction of extracellular signal-regulated signalling pathway (Thum et al 2008).…”