title: Angiotensin type 1 receptor blocker reduces intimal neovascularization and plaque growth in apolipoprotein E-deficient mice.
abstract: The interactions between the renin-angiotensin system and neovascularization in atherosclerotic plaque development are unclear. We investigated the effects of angiotensin II type 1 receptor antagonism in the pathogenesis of atherosclerosis in apolipoprotein E-deficient (ApoE(-/-)) mice with a special focus on plaque neovascularization. ApoE(-/-) mice fed a high-fat diet were randomly assigned to 1 of 2 groups and administered vehicle or olmesartan for 12 weeks. Quantification of plaque areas at the aortic root and in the thoracic and abdominal aorta revealed that, in all 3 of the regions, olmesartan reduced intimal neovessel density and the mRNA levels of toll-like receptor (TLR) 2 and TLR4. Olmesartan increased the levels of collagen and elastin, reduced the level of macrophages in the aortic root, and reduced the mRNA and the activity of matrix metalloproteinase (MMP) 2 in aortic roots and thoracic aortas. Aortic ring assay revealed that olmesartan-treated ApoE(-/-) mice had a markedly lower angiogenic response than that of untreated ApoE(-/-) mice. Bone marrow-derived endothelial progenitor cell-like c-Kit(+) cells from olmesartan-treated ApoE(-/-) mice showed marked impairment of cellular functions and lower expression of TLR2/TLR4 and MMP-2 compared with those of untreated controls. MMP-2 deficiency reduced intimal neovessel density and atherosclerotic lesion formation. Olmesartan and small-interfering RNA targeting TLR2 reduced the levels of TLR2, and MMP-2 mRNA induced angiotensin II in cultured endothelial cells. Angiotensin II type 1 receptor antagonism appears to inhibit intimal neovascularization in ApoE(-/-) mice, partly by reducing TLR2/TLR4-mediated inflammatory action and MMP activation, thus decreasing atherosclerotic plaque growth and increasing plaque instability.
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, Japan. chengxw0908@yahoo.com.cn
authors.forename: Xian Wu
authors.initials: XW
authors.lastname: Cheng
authors.forename: Haizhen
authors.initials: H
authors.lastname: Song
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sasaki
authors.forename: Lina
authors.initials: L
authors.lastname: Hu
authors.forename: Aiko
authors.initials: A
authors.lastname: Inoue
authors.forename: Yasuko K
authors.initials: YK
authors.lastname: Bando
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kuzuya
authors.forename: Kenji
authors.initials: K
authors.lastname: Okumura
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
mesh_terms: D000704:Analysis of Variance; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004041:Dietary Fats; D004797:Enzyme-Linked Immunosorbent Assay; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D034741:RNA, Small Interfering; D011897:Random Allocation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013777:Tetrazoles / Q000494:pharmacology*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D017539:Tunica Intima / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001057:Apolipoproteins E; D004041:Dietary Fats; D007093:Imidazoles; D034741:RNA, Small Interfering; D013777:Tetrazoles; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C437965:olmesartan; D020778:Matrix Metalloproteinase 2