Kincer Jeanie F, Uittenbogaard Annette, Dressman James, Guerin Theresa M, Febbraio Maria, Guo Ling, Smart Eric J
University of Kentucky Medical School, Department of Physiology, Lexington, Kentucky 40536, USA.
J Biol Chem. 2002 Jun 28;277(26):23525-33. doi: 10.1074/jbc.M202465200. Epub 2002 Apr 25.
Numerous studies have implicated either the presence or absence of CD36 in the development of hypertension. In addition, hypercholesterolemia is associated with the loss of nitric oxide-induced vasodilation and the subsequent increase in blood pressure. In the current study, we tested the hypothesis that diet-induced hypercholesterolemia promotes the disruption of agonist-stimulated nitric oxide generation and vasodilation in a CD36-dependent manner. To test this, C57BL/6, apoE null, CD36 null, and apoE/CD36 null mice were maintained on chow or high fat diets. In contrast to apoE null mice fed a chow diet, apoE null mice fed a high fat diet did not respond to acetylcholine with a decrease in blood pressure. Caveolae isolated from in vivo vessels did not contain endothelial nitric-oxide synthase and were depleted of cholesterol. Age-matched apoE/CD36 null mice fed a chow or high fat diet responded to acetylcholine with a decrease in blood pressure. The mechanism underlying the vascular dysfunction was reversible because vessels isolated from apoE null high fat-fed mice regained responsiveness to acetylcholine when incubated with plasma obtained from chow-fed mice. Further analysis demonstrated that the plasma low density lipoprotein fraction was responsible for depleting caveolae of cholesterol, removing endothelial nitric-oxide synthase from caveolae, and preventing nitric oxide production. In addition, the pharmacological removal of caveola cholesterol with cyclodextrin mimicked the effects caused by the low density lipoprotein fraction. We conclude that the ablation of CD36 prevented the negative impact of hypercholesterolemia on agonist-stimulated nitric oxide-mediated vasodilation in apoE null mice. These studies provide a direct link between CD36 and the early events that underlie hypercholesterolemia-mediated hypertension and mechanistic linkages between CD36 function, nitric-oxide synthase activation, caveolae integrity, and blood pressure regulation.
众多研究表明，CD36的存在与否与高血压的发生发展有关。此外，高胆固醇血症与一氧化氮诱导的血管舒张功能丧失及随后的血压升高有关。在本研究中，我们检验了以下假设：饮食诱导的高胆固醇血症以CD36依赖的方式促进激动剂刺激的一氧化氮生成和血管舒张的破坏。为验证这一点，将C57BL/6、载脂蛋白E基因敲除、CD36基因敲除和载脂蛋白E/CD36双基因敲除小鼠分别喂以普通饲料或高脂饲料。与喂食普通饲料的载脂蛋白E基因敲除小鼠不同，喂食高脂饲料的载脂蛋白E基因敲除小鼠对乙酰胆碱无血压下降反应。从体内血管分离的小窝不含内皮型一氧化氮合酶且胆固醇含量降低。年龄匹配的喂食普通饲料或高脂饲料的载脂蛋白E/CD36双基因敲除小鼠对乙酰胆碱有血压下降反应。血管功能障碍的潜在机制是可逆的，因为从喂食高脂饲料的载脂蛋白E基因敲除小鼠分离的血管在与喂食普通饲料小鼠的血浆孵育后恢复了对乙酰胆碱的反应性。进一步分析表明，血浆低密度脂蛋白部分导致小窝胆固醇耗竭，从小窝中去除内皮型一氧化氮合酶，并阻止一氧化氮生成。此外，用环糊精药理学去除小窝胆固醇模拟了低密度脂蛋白部分所引起的效应。我们得出结论，CD36的缺失可防止高胆固醇血症对载脂蛋白E基因敲除小鼠中激动剂刺激的一氧化氮介导的血管舒张产生负面影响。这些研究提供了CD36与高胆固醇血症介导的高血压潜在早期事件之间的直接联系，以及CD36功能、一氧化氮合酶激活、小窝完整性和血压调节之间的机制联系。
