慢性间歇缺氧活化棕色脂肪促进易损斑块形成的机制研究

项目名称： 慢性间歇缺氧活化棕色脂肪促进易损斑块形成的机制研究

项目编号： No.81470492

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 吴小凡

作者单位： 首都医科大学

项目金额： 73万元

中文摘要： 易损斑块导致急性冠脉综合症。近期发现慢性间歇低氧可升高LDL-C水平、促进易损斑块进展。我们前期研究显示，改善低氧可降低阻塞性睡眠呼吸暂停患者LDL-C水平和心脏事件发生率。但是低氧促进易损斑块进展机制仍不清楚。本研究将通过1）前瞻性队列研究：采用血管内超声研究睡眠呼吸暂停与易损斑块的相关性，以阐明缺氧与易损斑块的关系；2）构建apoE-/-、LDLR-/-小鼠，采用肾上腺素能受体激动剂/抑制剂，研究激动剂对小鼠易损斑块的影响，以及抑制剂是否能阻断缺氧对小鼠易损斑块的影响，以明确肾上腺素-β3肾上腺素受体在缺氧致易损斑块中的作用；3）构建apoE-/-UCP1-/-小鼠，探讨UCP1敲除后，低氧是否促进易损斑块形成，揭示UCP1在缺氧加剧易损斑块进程中的作用。本研究将阐明阻塞性睡眠呼吸暂停致急性冠脉综合症的分子机制，为寻找和筛选新的治疗靶点提供重要的科学依据。

中文关键词： 急性冠脉综合症；易损斑块；慢性间歇缺氧；虚拟组织学血管内超声；棕色脂肪

英文摘要： Vulnerable plaque is the pathophysiological basis of acute coronary syndrome. Recent studies have shown that chronic intermittent hypoxia can increase LDL-C levels and promote the development of vulnerable plaque. Our preliminary study reveals that improving hypoxia may reduce the LDL-C level and major adverse cardiac events rate in patients with both acute coronary syndrome and obstructive sleep apnea. However, the mechanism that chronic intermittent hypoxia affects lipid metabolism and accelerates the development of vulnerable remains unclear. In order to verify the mechanism, we will 1) evaluate the relationship between obstructive sleep apnea and coronary vulnerable plaque in patients with both acute coronary syndrome and obstructive sleep apnea in a prospective cohort study using virtual histology intravascular ultrasound, to clarify the impact of chronic intermittent hypoxia on vulnerable plaque ; 2) explore that if β3-adrenoceptor agonist (CL316243) has similar effect on the apoE-/- mice as chronic intermittent hypoxia stimulus, as well as if β3-adrenoceptor antiagonist (SR59230A) could block the effect of chronic intermittent hypoxia on the apoE-/- mice, to clarify the role of norepinephrine and β3-adrenoceptor in hypoxia induced vulnerable plaque ; 3) explore that if the deletion of UCP1 gene could impact the hypoxia effects on the vulnerable plaque development using apoE-/-UCP1-/- double knockout mice, to reveal the exact role of UCP1 in hypoxia accelerating vulnerable plaque progress. The current study will clarify the relationship between obstructive sleep apnea and vulnerable plaque, reveal the exact molecular mechanism of obstructive sleep apnea promoting acute coronary syndrome, and provide essential scientific basis for searching and screening of new therapeutic targets.

英文关键词： acute coronary syndrome;vulnerable plaque;chronic intermittent hypoxia;virtual histology intravascular ultrasound;brown adipose tissue