Alterations in Cardiac Connexin Expression in Cardiomyopathies

Abstract

Gap junctions, assembled from connexins, form the cell-to-cell pathways for propagation of the precisely orchestrated patterns of current flow that govern the synchronized rhythm of the healthy heart. As in most tissues and organs, multiple connexin types are co-expressed in the heart; the connexins Cx43, Cx40 and Cx45 are found in distinctive combinations and relative quantities in different, functionally specialized subsets of cardiomyocytes. Alterations in connexin expression and gap junction organization, now a well-documented feature of human cardiomyopathies, potentially contribute to the pro-arrhythmic substrate. In the diseased ventricle, the most consistently reported quantitative alteration involves heterogeneous reduction in Cx43 expression and disruption of the normal ordered pattern of Cx43 gap junction distribution. Additional studies suggest that upregulation of Cx40 and Cx45 may also feature in the failing ventricle, the former restricted to ischemic cardiomyopathy and localized to the subendocardial region. By correlating data from studies on the human patient with those from animal and cell models, alterations in connexin expression and gap junction organization have emerged as important factors to be considered in understanding the pro-arrhythmic substrate found in human cardiomyopathies.

Similar Transcriptomic Alterations in Cx43 Knockdown and Knockout Astrocytes

“…As an initial approach to explore this question in the Cx43 null setting, we have compared transcriptomic alterations with respect to wild-type cortical astrocytes (hereafter denoted by WT) in Cx43 null astrocytes (KO) and WT astrocytes acutely treated (48 h) with Cx43 siRNA (SI). Our findings indicate significantly similar transcriptional changes in Cx43 KO astrocytes and those treated acutely with siRNA, from which we infer that such changes may play important roles both in disorders related to hereditary connexin deficiency (for reviews see Gerido and White 2004;Harris 2007;Willecke et al 2002) and in pathological settings in which connexin expression is acutely, chronically, or intermittently altered, such as myocardial infarction (for reviews see Fishman 2005;Severs et al 2006) and multiple sclerosis (Brand-Schieber et al 2005;Roscoe et al 2007). …”

The Second PDZ Domain of Zonula Occludens-1 Is Dispensable for Targeting to Connexin43 Gap Junctions

“…The processes that determine GJ organization are conspicuously active during postnatal cardiac growth (Angst et al 1997;Gourdie et al 1992) and appear to go awry in certain diseases of the heart, contributing to the de-velopment of arrhythmias (Severs et al 2006). Currently a gulf exists between our understanding of diseased states and the specific alterations in GJ organization that may contribute to them.…”

Functional consequences of co-expressing connexin40 or connexin45 with connexin43 on intercellular electrical coupling

“…Disruption of gap junction distribution and remodeling of connexin expression are consistent features of human heart disease [29].…”