Atorvastatin increases myocardial indices of oxidative stress in a porcine model of hypercholesterolemia and chronic ischemia
Atorvastatin increases myocardial indices of oxidative stress in a porcine model of hypercholesterolemia and chronic ischemia
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DOI：
10.1111/j.1540-8191.2008.00600.x
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发表时间：
2008-07-01
影响因子：
1.6
通讯作者：
Sellke, Frank W.
中科院分区：
文献类型：
--
作者：
Sodha, Neel R.;Boodhwani, Munir;Sellke, Frank W.
背景/目的：阿托伐他汀先前已被证明可以减少猪模型中慢性缺血的内源性血管生成反应。这种效应的一个可能机制是一氧化氮的生物利用度降低，一氧化氮是血管生成的关键介质，继发于氧自由基增加。我们试图确定阿托伐他汀是否调节心肌组织的氧化应激。研究方法：在尤卡坦猪中进行了20周的高胆固醇血症饮食诱导，给药动物接受阿托伐他汀3 mg/kg/天。通过在20周龄时在近端回旋动脉周围手术放置Ameroid缩窄环诱导慢性心肌缺血，然后在27周龄时采集组织。进行心肌蛋白质、脂质和氧化应激的DNA生物标志物水平、血清8-异前列腺素水平、一氧化氮（NO）依赖性和非依赖性冠状动脉微血管反应性，以及同位素标记微球心肌灌注分析和内皮细胞密度的组织学分析。结果：阿托伐他汀治疗与心肌蛋白氧化和脂质过氧化水平升高有关。相反，血清氧化应激生物标志物并未升高。阿托伐他汀治疗改善了一氧化氮依赖性和非依赖性微血管反应性，并与缺血心肌区域灌注减少相关。结论：阿托伐他汀治疗与心肌组织蛋白和脂质氧化应激生物标志物水平升高、功能性内源性血管生成反应降低相关，但改善了冠状动脉微血管反应性。组织中氧化应激的增加可能在其他研究中观察到的阿托伐他汀治疗的血管生成反应降低中发挥作用。
Background/Aim: Atorvastatin has previously been shown to reduce the endogenous angiogenic response to chronic ischemia in a porcine model. One possible mechanism for this effect is reduced bioavailability of nitric oxide, a key mediator of angiogenesis, secondary to increased oxygen free radicals. We sought to determine if atorvastatin modulates oxidative stress in myocardial tissue. Methods: Dietary induction of hypercholesterolemia was performed over 20 weeks in Yucatan swine with treated animals receiving atorvastatin 3 mg/kg/day. Chronic myocardial ischemia was induced via surgical placement of an ameroid constrictor ring around the proximal circumflex artery at age 20 weeks, followed by tissue harvest at age 27 weeks. Myocardial levels of protein, lipid, and DNA biomarkers of oxidative stress, serum levels of 8-isoprostane, nitric oxide (NO) dependent, and independent coronary microvascular reactivity, as well as isotope-labeled microsphere myocardial perfusion analysis and histologic analysis for endothelial cell density was performed. Results: Atorvastatin treatment was associated with elevated levels of myocardial protein oxidation and lipid peroxidation. Conversely, serum oxidant stress biomarkers were not elevated. Atorvastatin treatment improved nitric oxide dependent and independent microvascular reactivity, and was associated with decreased perfusion in the ischemic myocardial territory. Conclusion: Treatment with atorvastatin was associated with increased levels of myocardial tissue protein and lipid oxidative stress biomarkers and a reduced functional endogenous angiogenic response, but improved coronary microvascular reactivity. Increased oxidative stress in tissues may play a role in the reduced angiogenic response seen with atorvastatin treatment in other studies.