title: Modulation of matrix metalloproteinase-1, its tissue inhibitor, and nuclear factor-kappa B by losartan in hypercholesterolemic rabbits.
abstract: Upregulation of angiotensin II receptor, may be involved in the initiation and progression of atherosclerosis. To examine the contribution of AT1 receptor in the expression of matrix metalloproteinase-1 (MMP-1) and its tissue inhibitor (TIMP-2) in lipid-deposited arterial tissues, New Zealand white rabbits were given high-cholesterol chow (with losartan 25 mg/d or vehicle) for 10 weeks. Losartan reduced the areas of sudanophilia in the aorta of rabbits fed high-cholesterol diet (p < 0.01 vs. control). Losartan also significantly decreased the enhanced mRNA expression of MMP-1 and TIMP-2 in aortas of rabbits with high-cholesterol diet. Losartan-treated rabbits revealed a reduction in immunohistochemical expression of MMP-1, whereas TIMP-2 expression became localized to the intima. In addition, losartan treatment reduced the activation of NF-kappa B by inhibiting the degradation of its inhibitor I kappa-B alpha. These observations demonstrate that AT1 receptor blockade with losartan reduces lipid deposition and exerts potent inhibitory effects on NF-kappa B activation and modulates the expression of MMP-1 and TIMP-2 in hypercholesterolemic rabbits.
authors.affiliation: Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Health Care System, Little Rock, AR 72205-7199, USA.
authors.forename: Hongjiang
authors.initials: H
authors.lastname: Chen
authors.forename: Dayuan
authors.initials: D
authors.lastname: Li
authors.forename: Jawahar L
authors.initials: JL
authors.lastname: Mehta
mesh_terms: D000804:Angiotensin II / Q000235:genetics / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism; D001161:Arteriosclerosis / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D015153:Blotting, Western; D002784:Cholesterol / Q000097:blood; D004036:Diet, Atherogenic; D005786:Gene Expression Regulation / Q000187:drug effects; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D007150:Immunohistochemistry; D019808:Losartan / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D044140:Receptor, Angiotensin, Type 1; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism*; D017539:Tunica Intima / Q000378:metabolism; D017540:Tunica Media / Q000378:metabolism
chemical_list: D057911:Angiotensin Receptor Antagonists; D016328:NF-kappa B; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D019716:Tissue Inhibitor of Metalloproteinase-2; D002784:Cholesterol; D020781:Matrix Metalloproteinase 1; D019808:Losartan