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

Kyoko Umeji, Seiji Umemoto, Shinichi Itoh, Masakazu Tanaka, Shinji Kawahara, Tohru Fukai, Masunori Matsuzaki

Research output: Contribution to journalArticle

66 Scopus citations

Abstract

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-γ 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-γ 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-γ expression and activity. Importantly, Cu/ZnSOD activity was positively correlated with the PPAR-γ activity in the aorta (P < 0.005), both of which were negatively correlated with aortic stiffness (P < 0.05). Vascular Cu/ZnSOD and PPAR-γ may play a crucial role in the antiatherogenic effects of pitavastatin in hypercholesterolemia in vivo.

Original languageEnglish (US)
Pages (from-to)H2522-H2532
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume291
Issue number5
DOIs
StatePublished - Nov 24 2006
Externally publishedYes

Keywords

  • Antioxidant
  • Atherosclerosis
  • Peroxisome proliferator-activated receptor
  • Pleiotropic effects
  • Reactive oxygen species
  • Vascular dysfunction

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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