Sugidachi A, Ohno K, Jakubowski J A, Ito Y, Tomizawa A, Mizuno M
Rare Disease and LCM Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States.
TH Open. 2017 Aug 10;1(2):e92-e100. doi: 10.1055/s-0037-1605361. eCollection 2017 Jul.
Patients with acute coronary syndrome with diabetes mellitus (DM) exhibit an impaired platelet inhibitory response to clopidogrel which is only partially understood. DM was induced by the administration of streptozotocin (STZ) to 9-week-old mice. The antithrombotic effects of clopidogrel (10 mg/kg/d, orally × 5 days) were determined using a FeCl -induced thrombosis model employing wild-type (WT), apolipoprotein E (apoE)-deficient, and diabetic apoE-deficient mice at 21 weeks. Antiplatelet effects were determined using flow cytometry. The antithrombotic effects of clopidogrel were similar in WT and apoE-deficient mice but were attenuated in diabetic apoE-deficient mice with the percent inhibition of thrombus area (µm ) by clopidogrel being 85.5% (WT mice), 75.0% (apoE-deficient mice), and 1.9% (diabetic apoE-deficient mice). The time to first occlusion and lumen stenosis also reflected a significant loss of the antithrombotic effects of clopidogrel in diabetic apoE-deficient mice. Ex vivo platelet activation, which was assessed using ADP-induced expression of activated glycoprotein IIb/IIIa, was completely inhibited by clopidogrel in these three groups of mice. In contrast, the effect of clopidogrel on the ex vivo expression of platelet P-selectin induced by protease-activated receptor 4-activating peptide was diminished in diabetic apoE-deficient mice compared with that in WT and apoE-deficient mice. These data suggest that diabetic apoE-deficient mice may serve as a useful model to better understand the impaired responses to clopidogrel in patients with DM, which may partially reflect a reduction of the effect of clopidogrel on thrombin-induced platelet activation.
患有糖尿病（DM）的急性冠状动脉综合征患者对氯吡格雷的血小板抑制反应受损，目前对此仅部分了解。通过给9周龄小鼠注射链脲佐菌素（STZ）诱导糖尿病。在21周时，使用野生型（WT）、载脂蛋白E（apoE）缺陷型和糖尿病apoE缺陷型小鼠的FeCl₃诱导血栓形成模型，确定氯吡格雷（10mg/kg/d，口服×5天）的抗血栓作用。使用流式细胞术确定抗血小板作用。氯吡格雷在WT小鼠和apoE缺陷型小鼠中的抗血栓作用相似，但在糖尿病apoE缺陷型小鼠中减弱，氯吡格雷对血栓面积（μm²）的抑制百分比在WT小鼠中为85.5%，在apoE缺陷型小鼠中为75.0%，在糖尿病apoE缺陷型小鼠中为1.9%。首次闭塞时间和管腔狭窄也反映出氯吡格雷在糖尿病apoE缺陷型小鼠中的抗血栓作用显著丧失。在这三组小鼠中，氯吡格雷完全抑制了用ADP诱导的活化糖蛋白IIb/IIIa表达来评估的体外血小板活化。相比之下，与WT小鼠和apoE缺陷型小鼠相比，氯吡格雷对蛋白酶激活受体4激活肽诱导的血小板P选择素体外表达的作用在糖尿病apoE缺陷型小鼠中减弱。这些数据表明，糖尿病apoE缺陷型小鼠可能是一个有用的模型，有助于更好地理解糖尿病患者对氯吡格雷反应受损的情况，这可能部分反映了氯吡格雷对凝血酶诱导的血小板活化作用的降低。
