Randriamboavonjy Voahanginirina, Pistrosch Frank, Bölck Birgit, Schwinger Robert H G, Dixit Madhulika, Badenhoop Klaus, Cohen Richard A, Busse Rudi, Fleming Ingrid
Vascular Signaling Group, and Institut für Kardiovaskuläre Physiologie, Johann Wolfgang Goethe-Universität, Frankfurt, Germany.
Circulation. 2008 Jan 1;117(1):52-60. doi: 10.1161/CIRCULATIONAHA.107.719807. Epub 2007 Dec 10.
Platelets from patients with type 2 diabetes mellitus display hyperaggregability and increased thrombogenic potential.
In platelets from patients with type 2 diabetes mellitus, we found enhanced tyrosine nitration and inactivation of the sarcoplasmic endoplasmic reticulum Ca2+-ATPase (SERCA-2), elevated platelet [Ca2+]i, and activation of mu-calpain. The tyrosine nitration of SERCA-2 and the activation of mu-calpain in vitro in platelets from healthy volunteers could be evoked in vitro by peroxynitrite. Platelet endothelial cell adhesion molecule-1 was identified as a mu-calpain substrate; its in vitro degradation was stimulated by peroxynitrite and prevented by calpain inhibitors. Calpain activation also was linked to hyperresponsiveness to thrombin and the loss of platelet sensitivity to nitric oxide synthase inhibitors. Platelets from patients with type 2 diabetes mellitus (hemoglobin A1c >6.6%) contained little or no intact platelet endothelial cell adhesion molecule-1, whereas degradation products were detectable. The peroxisome proliferator-activated receptor-gamma agonist rosiglitazone increased SERCA-2 expression in megakaryocytes, and treating patients with type 2 diabetes mellitus with rosiglitazone for 12 weeks increased platelet SERCA-2 expression and Ca2+-ATPase activity, decreased SERCA-2 tyrosine nitration, and normalized platelet [Ca2+]i. Rosiglitazone also reduced mu-calpain activity, normalized platelet endothelial cell adhesion molecule-1 levels, and partially restored platelet sensitivity to nitric oxide synthase inhibition.
These data identify megakaryocytes/platelets as additional cellular targets for peroxisome proliferator-activated receptor-gamma agonists and highlight potential benefits of rosiglitazone therapy in cardiovascular diseases.
2型糖尿病患者的血小板表现出高聚集性和血栓形成潜能增加。
在2型糖尿病患者的血小板中，我们发现酪氨酸硝化增强以及肌浆网Ca2+ -ATP酶（SERCA - 2）失活，血小板[Ca2+]i升高，以及μ-钙蛋白酶激活。健康志愿者血小板中SERCA - 2的酪氨酸硝化和μ-钙蛋白酶的激活在体外可由过氧亚硝酸盐诱发。血小板内皮细胞黏附分子-1被鉴定为μ-钙蛋白酶的底物；其体外降解受到过氧亚硝酸盐的刺激，并被钙蛋白酶抑制剂所抑制。钙蛋白酶激活还与对凝血酶的高反应性以及血小板对一氧化氮合酶抑制剂的敏感性丧失有关。2型糖尿病患者（糖化血红蛋白A1c>6.6%）的血小板中几乎没有完整的血小板内皮细胞黏附分子-1，而可检测到降解产物。过氧化物酶体增殖物激活受体-γ激动剂罗格列酮增加巨核细胞中SERCA - 2的表达，用罗格列酮治疗2型糖尿病患者12周可增加血小板SERCA - 2的表达和Ca2+ -ATP酶活性，降低SERCA - 2酪氨酸硝化，并使血小板[Ca2+]i正常化。罗格列酮还降低了μ-钙蛋白酶活性，使血小板内皮细胞黏附分子-1水平正常化，并部分恢复了血小板对一氧化氮合酶抑制的敏感性。
这些数据确定巨核细胞/血小板是过氧化物酶体增殖物激活受体-γ激动剂的额外细胞靶点，并突出了罗格列酮治疗在心血管疾病中的潜在益处。
