title: Angiotensin II triggers release of leukotriene C4 in vascular smooth muscle cells via the multidrug resistance-related protein 1.
abstract: The multidrug resistance-related protein-1 (MRP1) is important for the management of oxidative stress in vascular cells in vivo. Substrates of MRP1 are, among others, glutathione and the leukotriene C(4) (LTC(4)), an eicosanoid and mediator of inflammation. Angiotensin (Ang) II infusion results in MRP1(-/-) mice compared to wild-type mice in improved endothelial function and reduced reactive oxygen species (ROS) formation. However, the interaction between Ang II, LTC(4) and MRP1 is not completely understood and has never been investigated in vitro. Ang II induced in vascular smooth muscle cells (VSMC) the release of LTC(4) and the generation of ROS. Pharmacologic inhibition of MRP1 via MK 571 significantly reduced Ang II-induced ROS release (L012-luminescence) in VSMC. The release of ROS after Ang II stimulation is inhibited, to a comparable degree, by blockade of the Cys-LT1 receptor with montelukast. Incubation of VSMC with recombined LTC(4) and Ang II caused enhanced rates of proliferation in VSMC. This effect can be rescued by either MRP1 or Cys-LT1 receptor inhibition. Accordingly, stimulation of VSMC with LTC(4) reduces intracellular levels of glutathione, but does not affect apoptosis. LTC(4) stimulation results in a significant activation of MRP1, but does not alter MRP1 expression. These findings indicate a connection between Ang II, MRP1 and LTC(4). Both, MRP1 and LTC(4), are potentially promising targets for atheroprotective therapy.
authors.affiliation: Medizinische Klinik und Poliklinik II, Innere Medizin, Universitätsklinikum Bonn, Sigmund Freud Str. 25, 53105, Bonn, Germany. cornelius.mueller@ukb.uni-bonn.de
authors.forename: Cornelius F H
authors.initials: CF
authors.lastname: Mueller
authors.forename: Marc Ulrich
authors.initials: MU
authors.lastname: Becher
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zimmer
authors.forename: Sven
authors.initials: S
authors.lastname: Wassmann
authors.forename: Barbara
authors.initials: B
authors.lastname: Keuler
authors.forename: Georg
authors.initials: G
authors.lastname: Nickenig
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism* / Q000502:physiology; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D001692:Biological Transport; D049109:Cell Proliferation; D002478:Cells, Cultured; D005978:Glutathione / Q000032:analysis; D017997:Leukotriene C4 / Q000378:metabolism*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D051381:Rats
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000804:Angiotensin II; D017997:Leukotriene C4; D005978:Glutathione
references.citation: Circulation. 2002 Jan 29;105(4):530-6
references.pmid: 11815439
references.citation: Respir Res. 2006 Mar 22;7:42
references.pmid: 16553950
references.citation: Science. 2001 Nov 30;294(5548):1871-5
references.pmid: 11729303
references.citation: Circulation. 2002 Jan 22;105(3):393-6
references.pmid: 11804998
references.citation: Circulation. 2008 Jun 3;117(22):2912-8
references.pmid: 18506003
references.citation: J Biol Chem. 2008 Oct 3;283(40):27079-88
references.pmid: 18667437
references.citation: Arterioscler Thromb Vasc Biol. 2007 Apr;27(4):762-8
references.pmid: 17272743
references.citation: Nature. 2000 Sep 14;407(6801):233-41
references.pmid: 11001066
references.citation: Oncogene. 2003 Oct 20;22(47):7537-52
references.pmid: 14576857
references.citation: J Neurochem. 2001 Jan;76(2):627-36
references.pmid: 11208926
references.citation: Nat Med. 1997 Nov;3(11):1275-9
references.pmid: 9359705
references.citation: Allergy. 2002;57 Suppl 72:16-9
references.pmid: 12144548
references.citation: Circ Res. 2005 Sep 30;97(7):637-44
references.pmid: 16123331
references.citation: Ann N Y Acad Sci. 2002 Nov;973:488-504
references.pmid: 12485918
references.citation: J Hypertens. 2002 Feb;20(2):263-72
references.pmid: 11821711
references.citation: Biochem Biophys Res Commun. 2003 Aug 29;308(3):668-72
references.pmid: 12914802