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Originally published online as doi:10.2353/ajpath.2009.090160 on July 16, 2009

Published online before print July 16, 2009
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(American Journal of Pathology. 2009;175:916-924.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.090160

Oxidized Phospholipid Species Promote in Vivo Differential Cx43 Phosphorylation and Vascular Smooth Muscle Cell Proliferation

Scott R. Johnstone*, Jeremy Ross*, Michael J. Rizzo*, Adam C. Straub*, Paul D. Lampe{dagger}, Norbert Leitinger*{ddagger} and Brant E. Isakson*§

From the Robert M. Berne Cardiovascular Research Center,* Department of Pharmacology,{ddagger} and Department of Molecular Physiology and Biological Physics,§ University of Virginia School of Medicine, Charlottesville, Virginia; and the Fred Hutchinson Cancer Research Center,{dagger} Seattle Washington

Regulation of both the expression and function of connexins in the vascular wall is important during atherosclerosis. Progression of the disease state is marked by vascular smooth muscle cell (VSMC) proliferation, which coincides with the reduced expression levels of connexin 43 (Cx43). However, nothing is currently known about the factors that regulate post-translational modifications of Cx43 in atherogenesis, which could be of particular importance, due to the association between site-specific Cx43 phosphorylation and cellular proliferation. We compared the effects of direct carotid applications of two oxidized phospholipid derivatives, 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phosphorylcholine (POVPC) and 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphorylcholine (PGPC), on Cx43 expression and phosphorylation, and on cell proliferation. Since both POVPC and PGPC have been shown to act through different intracellular pathways, we hypothesized that each oxidized phospholipid species could induce differential Cx43 phosphorylation events in the cytoplasmically located carboxyl-terminal region of the protein, which could potentially enhance cell proliferation. Application of POVPC caused a reduction in VSMC Cx43 levels, enhanced its phosphorylation at serine (pS) 279/282, and increased VSMC proliferation both in vivo and in vitro. Treatment with PGPC enhanced VSMC pS368 levels with no associated change in proliferation. These oxidized phospholipid-induced Cx43 post-translational changes in VSMCs were consistent with those identified in ApoE–/– mice. Taken together, these results demonstrate that post-translational phosphorylation of Cx43 could be a key factor in the pathogenesis of atherosclerosis.




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