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Oxidized LDL and its Compound Lysophosphatidylcholine Potentiate AngII-Induced Vasoconstriction by Stimulation of RhoA

Jan Galle^*, Alexander Mameghani^*, Steffen-Sebastian Bolz, Stepan Gambaryan^*, Maria Görg^*, Thomas Quaschning^*, Ulrike Raff^*, Holger Barth, Stefan Seibold^*, Christoph Wanner^* and Ulrich Pohl

*Department of Medicine, Julius-Maximilians Universität, Würzburg, Germany; Department of Physiology, Ludwig-Maximilians Universität, München, Germany; Department of Experimental and Clinical Pharmacology and Toxicology, Albert-Ludwigs Universität Freiburg, Germany.

Correspondence to Prof. Dr. Jan Galle, Department of Medicine, University Hospital Würzburg, Joseph-Schneider-Str. 2, D-97080 Würzburg, Germany. Phone: 49-931-201-36331; Fax: 49-931-201-36502;

ABSTRACT. RhoA stimulates vascular tone by increasing smooth muscle Ca²⁺ sensitivity, e.g., in atherosclerosis. This study was an investigation of the influence of oxidized LDL (OxLDL), which accumulates in atherosclerotic plaques, on vascular tone induced by angiontensin II (AngII), with particular emphasis on the RhoA pathway. OxLDL had no influence on unstimulated vascular tone of isolated rabbit aorta, but it potentiated contractile responses induced by AngII. The Ca²⁺-antagonist felodipin partially prevented potentiation of contractile responses, whereas the AT₁ receptor antagonist losartan blunted AngII responses in presence and in absence of OxLDL. Rho-kinase inhibition by Y27632 abolished potentiation of contractile responses, and RhoA inhibition by C3-like transferase partially prevented it, suggesting that OxLDL activated RhoA. Activation of RhoA was further analyzed by detection of its translocation to the cell membrane after stimulation with OxLDL. Western blot analysis of aorta homogenates, as well as direct visualization in cultured smooth muscle cells using confocal laser scan microscopy, revealed that OxLDL potently activated RhoA. The effect of OxLDL was mimicked by its compound lysophosphatidylcholine, and C3 inhibited both lysophosphatidylcholine and OxLDL-induced RhoA stimulation. In conclusion, OxLDL stimulates the RhoA pathway, resulting in potentiation of AngII-induced vasoconstriction. Lysophosphatidylcholine mimics the OxLDL effect, consistent with a causal role of this OxLDL compound. Stimulation of RhoA by OxLDL may contribute to vasospasm in atherosclerotic arteries. E-mail: J-C.galle@mail.uni-wuerzburg.de

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