Ku D D, Dai J
Department of Pharmacology and Toxicology, University of Alabama at Birmingham, 35294, U.S.A.
J Cardiovasc Pharmacol. 1997 Nov;30(5):649-57. doi: 10.1097/00005344-199711000-00016.
Alpha-thrombin can alter vascular tone by proteolytic cleavage of its cell-surface receptor, which exposes a tethered peptide sequence, Ser-Phe-Leu-Leu-Arg-Asn (SFLLRN) that activates the receptor. We investigated the effects of increasing severity of coronary atherosclerosis on SFLLRN-induced responses on 165 human coronary artery rings isolated fresh from 15 patients who underwent cardiac transplantation. In 40 coronary rings with minimal intimal proliferation, addition of 0.001-5 microM SFLLRN resulted in a dose- and endothelium-dependent relaxation reaching a maximum of -87.0 +/- 2.3% (mean +/- SEM) and median inhibitory concentration (IC50) of 0.1 microM. Increasing severity of atherosclerotic lesion, as determined by morphometric quantification of intimal thickening under light microscopy, resulted in graded decreases in both sensitivity and magnitude of the observed relaxation. The maximal relaxations in coronary arteries with mild and moderate intimal proliferation were -76.7 +/- 3.5% (mean +/- SEM of 41 rings) and -63.6 +/- 6.4% (mean +/- SEM of 22 rings), respectively. In the 21 coronary rings with severe intimal proliferation, no significant SFLLRN-induced relaxation was noted. Mechanical disruption of intimal endothelium abolished the SFLLRN-induced relaxation observed in the minimal to mild intimally thickened arteries, whereas in arteries with moderate and severe intimal thickening, a significant SFLLRN-induced contraction (19 +/- 10% and 43 +/- 7%, respectively) was observed. Similar endothelium-dependent relaxations in minimal atherosclerotic and endothelium-independent contraction in severe atherosclerotic coronary arteries were also observed with alpha-thrombin. These findings confirm a recent in situ hybridization and immunohistochemistry study reporting localization of cloned thrombin receptors only in endothelium of "normal appearing" human abdominal aortae and induced expression of thrombin receptors in intimal/medial regions of the atherosclerotic vessels and further demonstrate that similar expression of thrombin receptors in human atherosclerotic coronary arteries leads to an unmasking of a marked vasoconstrictory response.
α-凝血酶可通过蛋白水解切割其细胞表面受体来改变血管张力，该受体暴露了一个拴系肽序列，即丝氨酸-苯丙氨酸-亮氨酸-亮氨酸-精氨酸-天冬酰胺（SFLLRN），它可激活该受体。我们研究了冠状动脉粥样硬化严重程度增加对从15例接受心脏移植患者新鲜分离的165条人冠状动脉环上SFLLRN诱导反应的影响。在40条内膜增殖极少的冠状动脉环中，添加0.001 - 5微摩尔/升的SFLLRN会导致剂量和内皮依赖性舒张，最大舒张可达-87.0±2.3%（平均值±标准误），半数抑制浓度（IC50）为0.1微摩尔/升。通过光学显微镜下内膜增厚的形态计量学量化确定的动脉粥样硬化病变严重程度增加，导致观察到的舒张的敏感性和幅度分级下降。内膜轻度和中度增殖的冠状动脉中的最大舒张分别为-76.7±3.5%（41条环的平均值±标准误）和-63.6±6.4%（22条环的平均值±标准误）。在21条内膜增殖严重的冠状动脉环中，未观察到明显的SFLLRN诱导的舒张。内膜内皮的机械破坏消除了在极少至轻度内膜增厚动脉中观察到的SFLLRN诱导的舒张，而在中度和重度内膜增厚的动脉中，观察到显著的SFLLRN诱导的收缩（分别为19±10%和43±7%）。用α-凝血酶也观察到在极少动脉粥样硬化的冠状动脉中类似的内皮依赖性舒张以及在严重动脉粥样硬化的冠状动脉中内皮非依赖性收缩。这些发现证实了最近的原位杂交和免疫组织化学研究，该研究报告克隆的凝血酶受体仅定位在“外观正常”的人腹主动脉内皮中，并在动脉粥样硬化血管的内膜/中膜区域诱导凝血酶受体表达，进一步证明人动脉粥样硬化冠状动脉中凝血酶受体的类似表达导致明显的血管收缩反应的暴露。
