Abstract 167: Pitavastatin Inhibits Aortic Stiffness by Reducing Oxidative Stress through the Activation of the Cu/Zn Superoxide Dismutase and Peroxisome Proliferator-Activated Receptor γ in Hypercholesterolemia in vivo
Background Statins might have lipid-lowering independent antiatherogenic properties including the inhibition of new-onset diabetes. Peroxisome proliferator-activated receptors (PPARs) may also play a crucial role in the glucose metabolism and atherosclerosis, and it is reported that the Cu/Zn superoxide dismutase (SOD) gene has a PPAR response element in its promoter region. However, it remains unclear whether lipophilic statin pitavastatin inhibits aortic stiffness by activating Cu/ZnSOD through PPARs. We hypothesized that pitavastatin inhibits aortic stiffness by modulating oxidative stress through the activation of Cu/ZnSOD via PPARγ activation in hypercholesterolemia.
Method and Results New Zealand white male rabbits were fed either normal chow or a 1% cholesterol (CHO) diet for 14 weeks. After the first 7 weeks, the CHO-fed rabbits were further divided into 3 groups: those fed with CHO-feed only (HC), those additionally given pitavastatin, and those additionally given an antioxidant, probucol. The extent of aortic stiffness was assessed by examining aortic stiffness parameter- β. Compared with the HC group, without affecting serum cholesterol or blood pressure levels, both the pitavastatin and probucol groups equally showed improved aortic stiffness by reducing aortic levels of reactive oxidative stress, nitrotyrosine, iNOS, and collagen, whereas PPARα or eNOS expression, or manganese SOD or ecSOD activities were equally restored in both drug-treated groups. Pitavastatin restored both Cu/ZnSOD activity (P<0.005) and PPARγ expression and activity (P<0.01), and inhibited NAD(P)H oxidase activity (P<0.0001) in the aorta, while probucol inhibited NAD(P)H oxidase activity more than did pitavastatin (P<0.0005) without affecting Cu/ZnSOD activity or PPARγ expression and activity. Furthermore, Cu/ZnSOD activity was positively correlated with the PPARγ activity in the aorta (P<0.005), both of which were negatively correlated with aortic stiffness (P<0.05).
Conclusions Pitavastatin inhibits aortic stiffness by reducing oxidative stress through the activation of the Cu/Zn superoxide dismutase and PPARγ in hypercholesterolemia in vivo.