Comparative effects of pitavastatin and probucol on oxidative stress, Cu/Zn superoxide dismutase, PPAR-gamma, and aortic stiffness in hypercholesterolemia.
Comparative effects of pitavastatin and probucol on oxidative stress, Cu/Zn superoxide dismutase, PPAR-gamma, and aortic stiffness in hypercholesterolemia.
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DOI：
10.1152/ajpheart.01198.2005
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发表时间：
2006-11
期刊：
影响因子：
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通讯作者：
Kyoko Umeji;S. Umemoto;S. Itoh;Masakazu Tanaka;S. Kawahara;T. Fukai;M. Matsuzaki
中科院分区：
文献类型：
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作者：
Kyoko Umeji;S. Umemoto;S. Itoh;Masakazu Tanaka;S. Kawahara;T. Fukai;M. Matsuzaki
受过氧化物酶体增殖物激活受体（PPAR）调节的活性氧清除酶铜/锌超氧化物歧化酶（SOD）在血管反应性中发挥着重要作用。然而，他汀类药物是否通过激活体内活性氧清除酶来恢复血管功能障碍仍不清楚。我们假设匹伐他汀通过激活高胆固醇血症中的 Cu/ZnSOD 和 PPAR-gamma 来调节氧化应激，从而恢复血管功能。新西兰白色雄性兔子被喂食正常食物或 1% 胆固醇 (CHO) 饮食 14 周。前 7 周后，将 CHO 喂养的兔子进一步分为三组：仅用 CHO 饲料 (HC) 喂养的组、另外给予匹伐他汀的组以及另外给予抗氧化剂普罗布考的组。通过检查主动脉僵硬度来评估动脉粥样硬化的程度。与 HC 组相比，匹伐他汀组和普罗布考组均通过降低主动脉反应性氧化应激、硝基酪氨酸和胶原水平来改善主动脉僵硬度，且不影响血清胆固醇或血压水平。匹伐他汀可恢复主动脉中的 Cu/ZnSOD 活性 (P < 0.005) 和 PPAR-gamma 表达和活性 (P < 0.01)，并抑制 NAD(P)H 氧化酶活性 (P < 0.0001)，而普罗布考比匹伐他汀更能抑制 NAD(P)H 氧化酶活性 (P < 0.0005)，而不影响 Cu/ZnSOD 活性或PPAR-γ 表达和活性。重要的是，Cu/ZnSOD 活性与主动脉中的 PPAR-gamma 活性呈正相关（P < 0.005），两者均与主动脉僵硬度呈负相关（P < 0.05）。血管 Cu/ZnSOD 和 PPAR-gamma 可能在匹伐他汀在体内高胆固醇血症中的抗动脉粥样硬化作用中发挥关键作用。
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-gamma 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-gamma 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-gamma expression and activity. Importantly, Cu/ZnSOD activity was positively correlated with the PPAR-gamma activity in the aorta (P < 0.005), both of which were negatively correlated with aortic stiffness (P < 0.05). Vascular Cu/ZnSOD and PPAR-gamma may play a crucial role in the antiatherogenic effects of pitavastatin in hypercholesterolemia in vivo.