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This Article Full Text Full Text (PDF) All Versions of this Article: 291/5/H2522    most recent 01198.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Umeji, K. Articles by Matsuzaki, M. Search for Related Content PubMed PubMed Citation Articles by Umeji, K. Articles by Matsuzaki, M.

Comparative effects of pitavastatin and probucol on oxidative stress, Cu/Zn superoxide dismutase, PPAR-, and aortic stiffness in hypercholesterolemia

¹Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine; ²Pharmaceutical Clinical Research Center, Yamaguchi University Hospital, Yamaguchi, Japan; and ³Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia

Submitted 12 November 2005 ; accepted in final form 19 June 2006

Reactive oxygen species-scavenging enzyme Cu/Zn superoxide dismutase (SOD) regulated by peroxisome proliferator-activated receptors (PPARs) plays an important role in vascular responsiveness. However, it remains unknown whether statin restores vascular dysfunction through the activation of reactive oxygen species-scavenging enzymes in vivo. We hypothesized that pitavastatin restores vascular function by modulating oxidative stress through the activation of Cu/ZnSOD and PPAR- in hypercholesterolemia. New Zealand White male rabbits were fed either normal chow or a 1% cholesterol (CHO) diet for 14 wk. After the first 7 wk, the CHO-fed rabbits were further divided into three groups: those fed with CHO feed only (HC), those additionally given pitavastatin, and those additionally given an antioxidant, probucol. The extent of atherosclerosis was assessed by examining aortic stiffness. When compared with the HC group, both the pitavastatin and probucol groups showed improved aortic stiffness by reducing aortic levels of reactive oxidative stress, nitrotyrosine, and collagen, without affecting serum cholesterol or blood pressure levels. Pitavastatin restored both Cu/ZnSOD activity (P < 0.005) and PPAR- expression and activity (P < 0.01) and inhibited NAD(P)H oxidase activity (P < 0.0001) in the aorta, whereas probucol inhibited NAD(P)H oxidase activity more than did pitavastatin (P < 0.0005) without affecting Cu/ZnSOD activity or PPAR- expression and activity. Importantly, Cu/ZnSOD activity was positively correlated with the PPAR- activity in the aorta (P < 0.005), both of which were negatively correlated with aortic stiffness (P < 0.05). Vascular Cu/ZnSOD and PPAR- may play a crucial role in the antiatherogenic effects of pitavastatin in hypercholesterolemia in vivo.

vascular dysfunction; atherosclerosis; pleiotropic effects; antioxidant; peroxisome proliferator-activated receptor; reactive oxygen species

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