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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2216.)
© 2006 American Heart Association, Inc.

Vascular Biology

Oxidized Phospholipids Alter Vascular Connexin Expression, Phosphorylation, and Heterocellular Communication

Brant E. Isakson; Gerhard Kronke; Alexandra Kadl; Norbert Leitinger; Brian R. Duling

From the Department of Molecular Physiology and Biological Physics (B.E.I., B.R.D.), Robert M. Berne Cardiovascular Research Center (B.E.I., G.K., A.K., N.L., B.R.D.), and Department of Pharmacology (N.L.), University of Virginia School of Medicine, Charlottesville.

Correspondence to Brant E. Isakson, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, PO Box 801394, Charlottesville, VA 22908. E-mail bei6n{at}virginia.edu

Objective— In endothelial cells (EC) and vascular smooth muscle cells (VSMC) from atherosclerotic mice, connexin (Cx) expression becomes distorted. Lipoprotein-derived phospholipid oxidation products (OxPAPC) play a critical role in atherosclerosis, and we hypothesized that they may act as trigger molecules causing the changes in connexin expression.

Methods and Results— We applied OxPAPC to murine carotid arteries in vivo and vascular cell cocultures. OxPAPC applied to carotids induced an upregulation of both Cx37 and Cx43 in the VSMC. In EC, Cx43 was upregulated and Cx37 was downregulated, whereas Cx40 in EC remained constant. In the vascular cell coculture, OxPAPC caused similar changes in Cx37 and Cx43 but caused a decrease in Cx40 in EC and an elevation of Cx40 in VSMC. In the coculture model, OxPAPC treatment led to the selective disappearance of Cx40 at the myoendothelial junction. Biocytin dye transfer between EC and VSMC coupling was dramatically reduced by OxPAPC. The decrease in dye transfer after OxPAPC treatment was correlated with an increase in tyrosine 265 phosphorylation of Cx43, especially at the in vitro myoendothelial junction.

Conclusions— We conclude that OxPAPC could be responsible for the changes in connexin expression previously reported in atherosclerosis.

Atherosclerosis has been associated with oxidized phospholipids (eg, OxPAPC) and changes in connexin expression. We demonstrate that OxPAPC alters connexin expression in endothelial cells and smooth muscle cells and at the in vitro myoendothelial junction. Once more, OxPAPC inhibited heterocellular communication, which coincided with phosphorylation of Cx43 at the myoendothelial junction.

Key Words: phospholipids • connexins • gap junctions • atherosclerosis • phosphorylation

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