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J Clin Invest. 2010 Jan;120(1):87-9. doi: 10.1172/JCI41780. Epub 2009 Dec 28.

Oxidant stress derails the cardiac connexon connection.

Author information

1
Department of Medicine, Johns Hopkins University School of Medicine, 720 Rutland Ave., Baltimore, Maryland 21205, USA. gtomasel@jhmi.edu

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.

PMID:
20038808
PMCID:
PMC2798705
DOI:
10.1172/JCI41780
[Indexed for MEDLINE]
Free PMC Article

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