Calkin Anna C, Drew Brian G, Ono Akiko, Duffy Stephen J, Gordon Michelle V, Schoenwaelder Simone M, Sviridov Dmitri, Cooper Mark E, Kingwell Bronwyn A, Jackson Shaun P
Diabetes Complications Laboratory, Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Rd Central, Melbourne, Australia 8008.
Circulation. 2009 Nov 24;120(21):2095-104. doi: 10.1161/CIRCULATIONAHA.109.870709. Epub 2009 Nov 9.
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.
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 approximately 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.
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.
糖尿病患者患心血管疾病的风险增加，且表现出血小板高反应性，这增加了他们对阿司匹林和氯吡格雷等抗血栓治疗的抵抗性。重组高密度脂蛋白（rHDL）对动脉粥样硬化斑块有短期有益作用，但它是否能有效降低糖尿病血小板的反应性尚不清楚。
对2型糖尿病患者输注安慰剂或rHDL（CSL-111；20mg·kg⁻¹·h⁻¹）4小时，导致血浆高密度脂蛋白胆固醇水平升高约1.4倍。输注rHDL与体外血小板对多种激动剂的聚集反应降低>50%相关，这种效应在洗涤后的血小板中持续存在。对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减弱以及流动条件下血栓形成减少50%。rHDL的分离磷脂成分可部分重现这些效应，其增强了血小板胆固醇流出并减少了脂筏组装。相比之下，rHDL的载脂蛋白AI成分对血小板功能、胆固醇流出或脂筏组装的影响最小。
这些发现表明，rHDL治疗在抑制糖尿病血小板的高反应性方面非常有效，部分原因是通过降低血小板膜的胆固醇含量。这些特性，再加上rHDL对动脉粥样硬化病变已知的短期有益作用，表明输注rHDL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。临床试验注册信息 - 网址：http://www.clinicaltrials.gov。唯一标识符：NCT00395148。
