Oxidant stress derails the cardiac connexon connection

Abstract

Connexin 43 (Cx43) is the major protein component of gap junctions that electrically couple cardiomyocytes at the intercalated disc. Oxidant stress, reduced Cx43 expression, and altered subcellular localization are present in many forms of structural heart disease. These changes in Cx43 lead to alterations in electrical conduction in the ventricle and predispose to lethal cardiac arrhythmias. In their study in this issue of the JCI, Smyth et al. tested the hypothesis that oxidant stress perturbs connexon forward trafficking along microtubules to gap junctions (see the related article beginning on page 266). Failing human ventricular myocardium exhibited a reduction in Cx43 and the microtubule-capping protein EB1 at intercalated discs. Oxidant stress in the adult mouse heart reduced N-cadherin, EB1, and Cx43 colocalization. In HeLa cells and neonatal mouse ventricular myocytes, peroxide exposure displaced EB1 from the plus ends of microtubules and altered microtubule dynamics. Mutational disruption of the EB1-tubulin interaction mimicked the effects of oxidant stress, including a reduction in surface Cx43 expression. These data provide important new molecular insights into the regulation of Cx43 at gap junctions and may identify targets for preservation of cellular coupling in the diseased heart.

Figure 1. Structure of the cardiac intercalated disc.

(A) A schematic of the intercalated disc under normal conditions shows normal forward trafficking along microtubules of Cx43-containing connexons to the adherens junction for incorporation into gap junction plaques between cardiomyocytes. Connexins mediate electrical conduction between cells and are thus central to cardiomyocyte excitation and contraction. (B) In this issue of the JCI, Smyth et al. (9) show that in the setting of oxidative stress, the microtubule-capping protein EB1 dissociates from the microtubule plus end, impeding connexon trafficking to the adherens junction and reducing the generation of gap junction channels. This results in cellular uncoupling and slowed electrical conduction in the ventricle and may predispose to lethal cardiac arrhythmias. Adapted with permission from Cell (10) and ref. .