Thrombin activation requires assembly of a prothrombinase complex of activated coagulation factors on an anionic phospholipid surface, classically provided by activated platelets. We have previously shown that anionic phosphatidylserine is exposed by rat vascular smooth muscle cells (VSMCs) undergoing apoptosis after serum withdrawal. In this study, using a chromogenic assay, we have shown thrombin generation by apoptotic VSMCs expressing c-myc (VSMC-myc) with an area under the thrombin-generation curve (AUC) of 305 +/- 17 nmol x min/L and a peak thrombin (PT) of 154 +/- 9 nmol/L. The thrombin-generating potential of the apoptotic VSMC-myc cells was greater than that of unactivated platelets (P = .003 for AUC; P = .0002 for PT) and similar to calcium-ionophore activated platelets (AUC of 332 +/- 15 nmol x min/L, P = .3; PT of 172 +/- 8 nmol/L, P = .2). Thrombin activation was also seen with apoptotic human VSMCs (AUC of 211 +/- 8 nmol x min/L; PT of 103 +/- 4 nmol/L) and was inhibited by annexin V (P < .0001 for AUC and PT). VSMC-myc cells maintained in serum generated less thrombin than after serum withdrawal (P = .0002 for AUC and PT). VSMCs derived from human coronary atherosclerotic plaques that apoptose even in serum also generated thrombin (AUC of 260 +/- 2 nmol x min/L; PT of 128 +/- 4 nmol/L). We conclude that apoptotic VSMCs possess a significant thrombin-generating capacity secondary to phosphatidylserine exposure. Apoptotic cells within atherosclerotic plaques may allow local thrombin activation, thereby contributing to disease progression.

译文

凝血酶的活化需要活化的凝血因子的凝血酶原酶复合物在阴离子磷脂表面上的组装,这通常是由活化的血小板提供的。先前我们已经表明,在撤离血清后,发生凋亡的大鼠血管平滑肌细胞(VSMC)暴露了阴离子磷脂酰丝氨酸。在这项研究中,我们使用生色测定法显示了表达c-myc(VSMC-myc)的凋亡VSMC的凝血酶生成,其凝血酶生成曲线(AUC)下方的面积为305 /-17 nmol x min / L,凝血酶峰值(PT)为154 9 nmol / L。凋亡的VSMC-myc细胞的凝血酶生成潜能大于未激活的血小板(对于AUC,P = .003;对于PT,P = .0002),类似于钙离子载体激活的血小板(AUC为332 /-15 nmol) xmin / L,P = 0.3; PT为172 / 8-nmol / L,P = 0.2)。在凋亡的人VSMC中也观察到凝血酶活化(AUC为211 /-8 nmol x min / L; PT为103 /-4 nmol / L),并被膜联蛋白V抑制(对于AUC和PT,P <.0001)。血清中维持的VSMC-myc细胞产生的凝血酶少于血清中止后产生的凝血酶(对于AUC和PT,P = .0002)。源自甚至在血清中也会凋亡的人冠状动脉粥样斑块的VSMC也会产生凝血酶(AUC为260/2 nmol x min / L; PT为128/4 nmol / L)。我们得出结论,凋亡性VSMC具有继磷脂酰丝氨酸暴露后的显着凝血酶生成能力。动脉粥样硬化斑块中的凋亡细胞可能允许局部凝血酶活化,从而促进疾病进展。

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