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

凝血酶激活需要在阴离子磷脂表面上组装活化的凝血因子的凝血酶原复合物,通常由活化的血小板提供。我们以前已经表明,阴离子磷脂酰丝氨酸被大鼠血管平滑肌细胞 (VSMCs) 暴露,在血清戒断后发生凋亡。在这项研究中,使用显色测定法,我们已经显示表达c-myc (VSMC-myc) 的凋亡VSMC产生凝血酶,凝血酶产生曲线 (AUC) 下面积为305 +/- 17 nmol × min/L,凝血酶峰 (PT) 为154 +/- 9 nmol/L。凋亡的VSMC-myc细胞的凝血酶生成潜力大于未激活的血小板 (AUC P = .003; PT P = .0002),与钙离子载体激活的血小板相似 (AUC为332 +/- 15 nmol x min/L,P = .3; PT为172 +/- 8 nmol/L,P = .2)。在凋亡的人VSMCs中也可以看到凝血酶活化 (AUC为211 +/- 8 nmol × min/L; PT为103 +/- 4 nmol/L),并被膜联蛋白V抑制 (P < .0001 AUC和PT)。维持在血清中的VSMC-myc细胞产生的凝血酶少于血清戒断后 (对于AUC和PT,P = .0002)。来源于人冠状动脉粥样硬化斑块的VSMCs,即使在血清中凋亡也产生凝血酶 (AUC为260 +/- 2 nmol × min/L; PT为128 +/- 4 nmol/L)。我们得出的结论是,凋亡的VSMCs在磷脂酰丝氨酸暴露后具有显着的凝血酶生成能力。动脉粥样硬化斑块内的凋亡细胞可能会激活局部凝血酶,从而促进疾病进展。

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