Reconstituted High-Density Lipoprotein Attenuates Platelet Function in Individuals With Type 2 Diabetes Mellitus by Promoting Cholesterol Efflux
Reconstituted High-Density Lipoprotein Attenuates Platelet Function in Individuals With Type 2 Diabetes Mellitus by Promoting Cholesterol Efflux
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DOI：
10.1161/circulationaha.109.870709
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发表时间：
2009-11-24
期刊：
影响因子：
37.8
通讯作者：
Jackson, Shaun P.
中科院分区：
文献类型：
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作者：
Calkin, Anna C.;Drew, Brian G.;Jackson, Shaun P.
背景-糖尿病患者患心血管疾病的风险增加，并表现出血小板高反应性，增加了他们对抗血栓治疗如阿司匹林和氯吡格雷的抵抗。重组高密度脂蛋白（rHDL）对动脉粥样硬化斑块有短期的有益作用，但它是否能有效地降低糖尿病血小板的反应性尚不清楚。kg（-1）。h（-1））4小时，导致血浆HDL胆固醇水平增加约1.4倍。rHDL输注与对多种激动剂的离体血小板聚集反应减少>50%相关，这种作用在洗涤的血小板中持续存在。健康个体血小板的体外研究表明，rHDL对血小板功能的抑制作用具有时间和剂量依赖性，并导致血小板功能广泛衰减，血流下血栓形成减少50%。这些作用可以概括，部分，由分离的磷脂成分的rHDL，增强流出的胆固醇从血小板和减少脂筏组装。相比之下，载脂蛋白AI成分的rHDL对血小板功能，胆固醇流出，或脂筏assembly.Conclusion-These研究结果表明，rHDL治疗是非常有效的抑制糖尿病血小板的反应性提高，部分通过降低血小板膜的胆固醇含量。这些特性，结合已知的rHDL对动脉粥样硬化病变的短期有益作用，表明rHDL输注可能是减少糖尿病个体动脉粥样硬化血栓形成并发症的有效方法。http://www.clinicaltrials.gov（循环。2009;120：2095-2104）。
Background-Individuals with diabetes mellitus have an increased risk of cardiovascular disease and exhibit platelet hyperreactivity, increasing their resistance to antithrombotic therapies such as aspirin and clopidogrel. Reconstituted high-density lipoprotein (rHDL) has short-term beneficial effects on atherosclerotic plaques, but whether it can effectively reduce the reactivity of diabetic platelets is not known.Methods and Results-Individuals with type 2 diabetes mellitus were infused with placebo or rHDL (CSL-111; 20 mg . kg(-1) . h(-1)) for 4 hours, resulting in an approximate to 1.4-fold increase in plasma HDL cholesterol levels. rHDL infusion was associated with a >50% reduction in the ex vivo platelet aggregation response to multiple agonists, an effect that persisted in washed platelets. In vitro studies in platelets from healthy individuals revealed that the inhibitory effects of rHDL on platelet function were time and dose dependent and resulted in a widespread attenuation of platelet function and a 50% reduction in thrombus formation under flow. These effects could be recapitulated, in part, by the isolated phospholipid component of rHDL, which enhanced efflux of cholesterol from platelets and reduced lipid raft assembly. In contrast, the apolipoprotein AI component of rHDL had minimal effect on platelet function, cholesterol efflux, or lipid raft assembly.Conclusion-These findings suggest that rHDL therapy is highly effective at inhibiting the heightened reactivity of diabetic platelets, partly through reducing the cholesterol content of platelet membranes. These properties, combined with the known short-term beneficial effects of rHDL on atherosclerotic lesions, suggest that rHDL infusions may be an effective approach to reduce atherothrombotic complications in diabetic individuals.Clinical Trial Registration Information-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00395148. (Circulation. 2009;120:2095-2104.)