title: Angiotensin II stimulates matrix metalloproteinase secretion in human vascular smooth muscle cells via nuclear factor-kappaB and activator protein 1 in a redox-sensitive manner.
abstract: The renin-angiotensin system contributes to atherogenesis. Matrix metalloproteinases (MMP) are thought to participate in plaque destabilization through degradation of extracellular matrix. This study tested whether angiotensin II (ANG II) induces MMP in human vascular smooth muscle cells (SMC). ANG II induced expression of MMP-1, -3, and -9, but not of MMP-2 in SMC. The expression of MMP-1, a key enzyme for collagen degradation, was studied in detail. SMC stimulated with ANG II concentration-dependently released enzymatically active MMP-1. The ANG II type 1 receptor antagonists losartan and candesartan blocked ANG-II-induced MMP-1 release. Inhibition experiments with actinomycin D suggest ANG-II-induced MMP-1 mRNA regulation at the transcriptional level. Decoy oligodeoxynucleotides against nuclear factor-kappaB and activator protein 1 inhibited MMP-1 secretion, demonstrating participation of these transcription factors in MMP-1 transcription. Stimulation of MMP-1 by ANG II depended on cyclooxygenase 2. The antioxidants pyrrolidine dithiocarbamate and N-acetylcysteine, the flavin protein inhibitor diphenylene iodonium, and the NADP(H) oxidase inhibitor apocynin blocked MMP-1 release, suggesting a redox-sensitive mechanism involving NADP(H) oxidase. The reactive oxygen species (ROS) donor 2,3-dimethoxy-1,4-naphthoquinone induced MMP-1 secretion and enhanced ANG-II-stimulated MMP-1 expression. These findings indicate that ROS may increase their own production by activation of NADP(H) oxidase. The capability of ANG II to induce functionally active MMP in human SMC may contribute to the altered plaque composition seen in complicated stages of atherosclerosis.
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Browatzki
authors.forename: Dina
authors.initials: D
authors.lastname: Larsen
authors.forename: Carolein A H
authors.initials: CA
authors.lastname: Pfeiffer
authors.forename: Sven G
authors.initials: SG
authors.lastname: Gehrke
authors.forename: Joachim
authors.initials: J
authors.lastname: Schmidt
authors.forename: Alexander
authors.initials: A
authors.lastname: Kranzhofer
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Roger
authors.initials: R
authors.lastname: Kranzhofer
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D001161:Arteriosclerosis / Q000378:metabolism* / Q000503:physiopathology; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D016328:NF-kappa B / Q000378:metabolism*; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000032:analysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D012501:Saphenous Vein / Q000166:cytology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D016328:NF-kappa B; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D003094:Collagen; D020781:Matrix Metalloproteinase 1