This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 104/5/609    most recent CIRCRESAHA.108.186064v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Cherepanova, O. A. Articles by Owens, G. K. Search for Related Content PubMed PubMed Citation Articles by Cherepanova, O. A. Articles by Owens, G. K. Related Collections Smooth muscle proliferation and differentiation

(Circulation Research. 2009;104:609.)
© 2009 American Heart Association, Inc.

Molecular Medicine

Oxidized Phospholipids Induce Type VIII Collagen Expression and Vascular Smooth Muscle Cell Migration

Olga A. Cherepanova, Nataliya A. Pidkovka, Olga F. Sarmento, Tadashi Yoshida, Qiong Gan, Eser Adiguzel, Michelle P. Bendeck, Judith Berliner, Norbert Leitinger, Gary K. Owens

From the Departments of Molecular Physiology and Biological Physics (O.A.C., O.F.S., T.Y., Q.G., G.K.O.) and Pharmacology (N.L.), Cardiovascular Research Center, University of Virginia, Charlottesville; Nephrology Division (N.A.P.), Vanderbilt University Medical Center, Nashville, Tenn; Department of Laboratory Medicine and Pathobiology (E.A., M.P.B.), University of Toronto, Ontario, Canada; and Department of Medicine/Division of Cardiology (J.B.), University of California, Los Angeles.

Correspondence to Dr Gary K. Owens, University of Virginia, Robert M. Berne Cardiovascular Research Center, 415 Lane Rd, MR5 RM 1328, Charlottesville, VA 22908. E-mail gko{at}virginia.edu

Phenotypic switching of vascular smooth muscle cells (VSMCs) is known to play a critical role in the development of atherosclerosis. However, the factors present within lesions that mediate VSMC phenotypic switching are unclear. Oxidized phospholipids (OxPLs), including 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine (POVPC), are active components of minimally modified low density lipoprotein and have been previously shown to induce multiple proatherogenic events in endothelial cells and macrophages, but their effects on VSMCs have been largely unexplored until recently. We previously showed that OxPLs induced phenotypic switching of VSMCs, including suppression of SMC differentiation marker genes. The goal of the present studies was to test the hypothesis that OxPLs alter extracellular matrix production and VSMC migration. Results showed that POVPC activated expression of several extracellular matrix proteins in VSMC. POVPC increased expression of type VIII collagen 1 chain (Col8a1) mRNA in cultured VSMCs and in vivo in rat carotid arteries by 9-fold and 4-fold, respectively. POVPC-induced activation of Col8a1 gene expression was reduced by small interfering RNA–mediated suppression of Krüppel-like factor 4 (Klf4) and Sp1, and was abolished in Klf4-knockout VSMCs. POVPC increased Klf4 binding to the Col8a1 gene promoter both in vivo in rat carotid arteries and in cultured VSMCs based on chromatin immunoprecipitation assays. Moreover, POVPC-induced VSMC migration was markedly reduced in Klf4- or type VIII collagen–knockout VSMCs. Given evidence that OxPLs are present within atherosclerotic lesions, it is interesting to suggest that OxPL-induced changes in VSMC phenotype may contribute to the pathogenesis of atherosclerosis at least in part through changes in extracellular matrix composition.

Key Words: POVPC • PGPC • PEIPC • type VIII collagen • Klf4 • vascular smooth muscle cell migration