title: Regression of atherosclerosis by amlodipine via anti-inflammatory and anti-oxidative stress actions.
abstract: We examined whether amlodipine, an L-type calcium channel blocker (CCB), has an inhibitory effect on oxidative stress and inflammatory response, and thereby atherosclerosis, in apolipoprotein E-deficient (ApoEKO) mice. Adult male ApoEKO mice (6 weeks of age) were fed a high-cholesterol diet (HCD) for 8 or 10 weeks with or without oral administration of amlodipine (3 mg/kg/day) for 10 weeks or for only the last 2 weeks of the HCD. After HCD feeding, atherosclerotic lesion formation, in situ superoxide production and nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity were evaluated in the proximal aorta. The expressions of NADPH oxidase subunits (p47(phox) and rac-1), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) were determined with immunohistochemistry and quantitative real-time reverse-transcription polymerase chain reaction. After 8 to 10 weeks of HCD administration to ApoEKO mice, marked atherosclerotic lesion formation was observed in the proximal aorta. In the atherosclerotic lesion, superoxide production, the expression of NADPH oxidase subunits, and NADPH oxidase activity were enhanced, and the expressions of MCP-1, ICAM-1, and VCAM-1 were increased. These changes were suppressed in mice that were treated with amlodipine for 10 weeks concomitant with HCD administration, with no significant change in blood pressure and plasma cholesterol level. We also observed that treatment with amlodipine for only the last 2 weeks regressed the atherosclerotic lesions with a decrease in oxidative stress and vascular inflammation. Inhibition of the atherosclerotic lesion area and lipid area in the proximal aorta by amlodipine was correlated with its inhibitory actions on oxidative stress, inflammation and the production of adhesive molecules. These results suggest that amlodipine not only inhibits atherosclerotic lesion formation, but also regresses atherosclerosis, and that these effects are at least partly due to inhibition of oxidative stress and inflammatory response.
authors.affiliation: Second Department of Internal Medicine, Ehime University School of Medicine, hitsukawa, Tohon, Japan.
authors.forename: Toyofumi
authors.initials: T
authors.lastname: Yoshii
authors.forename: Masaru
authors.initials: M
authors.lastname: Iwai
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.forename: Ayumi
authors.initials: A
authors.lastname: Ide
authors.forename: Shiori
authors.initials: S
authors.lastname: Fukunaga
authors.forename: Akira
authors.initials: A
authors.lastname: Oshita
authors.forename: Masaki
authors.initials: M
authors.lastname: Mogi
authors.forename: Jitsuo
authors.initials: J
authors.lastname: Higaki
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Horiuchi
mesh_terms: D017311:Amlodipine / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology; D050197:Atherosclerosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D013481:Superoxides / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D001057:Apolipoproteins E; D002121:Calcium Channel Blockers; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D002791:Cholesterol, Dietary; D019010:Vascular Cell Adhesion Molecule-1; D013481:Superoxides; D018799:Intercellular Adhesion Molecule-1; D017311:Amlodipine; D019255:NADPH Oxidases