title: Oxidized LDL and its compound lysophosphatidylcholine potentiate AngII-induced vasoconstriction by stimulation of RhoA.
abstract: RhoA stimulates vascular tone by increasing smooth muscle Ca(2+) 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 angiotensin 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 Ca(2+)-antagonist felodipin partially prevented potentiation of contractile responses, whereas the AT(1) 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.
authors.affiliation: Department of Medicine, Julius-Maximilians Universität, Würzburg, Germany. J-C.galle@mail.uni-wuerzburg.de
authors.forename: Jan
authors.initials: J
authors.lastname: Galle
authors.forename: Alexander
authors.initials: A
authors.lastname: Mameghani
authors.forename: Steffen-Sebastian
authors.initials: SS
authors.lastname: Bolz
authors.forename: Stepan
authors.initials: S
authors.lastname: Gambaryan
authors.forename: Maria
authors.initials: M
authors.lastname: Görg
authors.forename: Thomas
authors.initials: T
authors.lastname: Quaschning
authors.forename: Ulrike
authors.initials: U
authors.lastname: Raff
authors.forename: Holger
authors.initials: H
authors.lastname: Barth
authors.forename: Stefan
authors.initials: S
authors.lastname: Seibold
authors.forename: Christoph
authors.initials: C
authors.lastname: Wanner
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pohl
mesh_terms: D036002:ADP Ribose Transferases / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001692:Biological Transport / Q000187:drug effects; D002417:Cattle; D002478:Cells, Cultured; D003013:Clostridium; D004357:Drug Synergism; D015736:Felodipine / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D019808:Losartan / Q000494:pharmacology; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000378:metabolism / Q000502:physiology*
chemical_list: D000577:Amides; D047908:Intracellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL; D008244:Lysophosphatidylcholines; D011725:Pyridines; D014662:Vasoconstrictor Agents; C099252:oxidized low density lipoprotein; D000804:Angiotensin II; C108830:Y 27632; D036002:ADP Ribose Transferases; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D019808:Losartan; D015736:Felodipine