title: Endogenous angiotensin II enhances atherogenesis in apoprotein E-deficient mice with renovascular hypertension through activation of vascular smooth muscle cells.
abstract: Renovascular hypertension is one of the most important risk factors in the development of atherosclerosis. However, very little is known about the role of angiotensin II (AII), a key regulator of blood pressure homeostasis, on renovascular hypertension-associated atherogenesis. To study a possible role of AII on atherogenesis, we generated apoE-deficient hypertensive mice with either normal or increased AII production by applying 1-kidney, 1-clip (1K1C) or 2-kidney, 1-clip (2K1C) operation, respectively. Hypertension was successfully achieved in both mice groups, and was persistent for 8 weeks. Atherosclerosis quantification showed a marked increase in lesion area in aortic sinus of 2K1C mice as compared with 1K1C mice, suggesting a potential role of endogenous AII on atherogenesis. In the immunohistochemical analysis, induction of renovascular hypertension with 2K1C for 8 weeks led to an enhanced accumulation of macrophages in the aortic sinus, which was accompanied by a parallel increase in scavenger receptor A (SRA) expression on the macrophages. In in vitro experiments, although treatment of cells with increasing concentrations of AII (0.1 to 10 microM) affects neither SRA expression nor oxLDL uptake by macrophages, conditioned media (CM) derived from AII-stimulated vascular smooth muscle cells (VSMC) increased macrophage uptake of oxLDL in association with an enhanced expression of SRA on the macrophages. These findings suggest that the increased generation of AII in renovascular hypertension may initiate and promote atherosclerosis by activation of VSMC.
authors.affiliation: Department of Pharmacology, College of Medicine and Medical Research Center for Ischemic Tissue Regeneration, Pusan National University, Seo-Gu, Busan, Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Heo
authors.forename: Mi Ran
authors.initials: MR
authors.lastname: Yun
authors.forename: Keun Hwa
authors.initials: KH
authors.lastname: Jung
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Park
authors.forename: Seung Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Sun Sik
authors.initials: SS
authors.lastname: Bae
authors.forename: Won Suk
authors.initials: WS
authors.lastname: Lee
authors.forename: Chi Dae
authors.initials: CD
authors.lastname: Kim
mesh_terms: D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019084:Fluorescent Antibody Technique, Indirect; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020868:Gene Silencing; D006978:Hypertension, Renovascular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007091:Image Processing, Computer-Assisted; D007124:Immunoenzyme Techniques; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D012850:Sinus of Valsalva / Q000378:metabolism / Q000473:pathology
chemical_list: D001057:Apolipoproteins E; D015415:Biomarkers; D017077:Culture Media, Conditioned; D000804:Angiotensin II