Alterations of Phosphorylation State of Connexin 43 during Hypoxia and Reoxygenation are Associated with Cardiac Function

Satoshi Matsushita ¹, Hidetake Kurihara ^1*, Makino Watanabe ¹, Takao Okada ¹, Tatsuo Sakai ¹ and Atsushi Amano ¹

¹ Departments of Cardiovascular Surgery (SM,AA), Anatomy (HK,TS), and Physiology (MW,TO), Juntendo University School of Medicine, Tokyo, Japan

^* To whom correspondence should be addressed. E-mail: hidetake{at}med.juntendo.ac.jp.

Submitted on December 24, 2004
Accepted on 31 October 2005

	Abstract

Gap junctions formed by connexins mediate cell-cell communication by electrical and chemical coupling. Recently, it has been shown that alterations in the phosphorylation state of the connexins result in functional alteration of cell-cell communication through gap junctions. Therefore, we focused on the association of alterations of phosphorylation state of connexin 43 (Cx43) with cardiac function in vivo. Rat hearts were transferred to Langendorff apparatus and submitted to hypoxia and then reoxygenated. In the control heart, Cx43 was phosphorylated and located at the intercalated disc. When the hearts were subjected to hypoxia, Cx43 at gap junctions was dephosphorylated and changed its localization to the entire plasma membrane. The area of cardiomyocytes stained with anti-phosphorylated Cx43 antibody was decreased in time-dependent manner. Immunoblot data supported the decrease of phosphorylated Cx43 during hypoxia. ZO-1 did not change its localization at the intercalated disc during the hypoxic period. We also found that the area occupied by dephosphorylated Cx43 was correlated with the decrease of percent of rate-pressure product (%RPP). These data indicate that dephosphorylation and redistribution of Cx43 is an early sign of cardiac injury after hypoxia. The detection of dephosphorylated Cx43 may serve as a diagnostic tool for examining ischemic heart disease.

Key Words: Rat, heart, gap junction, cell-cell junction, Langendorff perfusion, immunohistochemistry, ZO-1

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