Department of Cardiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China.
Department of Cardiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China.
Arch Biochem Biophys. 2020 Sep 15;690:108460. doi: 10.1016/j.abb.2020.108460. Epub 2020 Jun 27.
Our previous research revealed that trypsin is abundantly expressed in atherosclerotic plaques and its distribution overlaps with that of matrix metalloproteinase-9 (MMP-9). This study was performed to explore the possible roles of trypsin in vulnerable atherosclerotic plaque formation.
Twenty-four rabbits were randomly assigned to a normal (control) group, an atherosclerosis (experimental) group and a trypsin inhibitor (aprotinin) group. In the 13th feeding week, the aprotinin group was treated with 5 mg/kg/day aprotinin via ear vein for 4 weeks. At the end of the 16th week, coronary arterial and aortic expression of trypsin, proteinase-activated receptor-2 (PAR-2), activated MMP-9, and pro-inflammatory cytokines were significantly greater in the experimental group than in the control group. Aprotinin decreased trypsin expression and activation in plaques, blocked PAR-2 and MMP-9 activation, and decreased cytokine expression; it also increased fibrous cap thickness, decreased the intima-media thickness and intimal/medial ratio, thus significantly ameliorating plaque vulnerability. Upregulated trypsin, MMP-9 and PAR-2 were also found in coronary intimal atherosclerotic plaques of patients undergoing coronary artery bypass grafting.
Ectopic trypsin was significantly upregulated in atherosclerotic plaques, which increased pro-inflammatory cytokine levels by activating PAR-2 and promoted plaque instability by activating proMMP-9, thereby promoting atherosclerosis and plaque vulnerability. In addition, the high trypsin expression in human coronary intimal atherosclerotic plaques suggests that targeting trypsin may be a new strategy for acute coronary syndrome prevention.
我们之前的研究表明，组织蛋白酶在动脉粥样硬化斑块中大量表达，其分布与基质金属蛋白酶-9（MMP-9）重叠。本研究旨在探讨组织蛋白酶在易损性动脉粥样硬化斑块形成中的可能作用。
24 只兔子被随机分为正常（对照组）、动脉粥样硬化（实验组）和胰蛋白酶抑制剂（抑肽酶）组。在第 13 周喂养期，实验组通过耳静脉每天给予 5mg/kg 抑肽酶 4 周。在第 16 周末，实验组的冠状动脉和主动脉中组织蛋白酶、蛋白酶激活受体-2（PAR-2）、激活的 MMP-9 和促炎细胞因子的表达明显高于对照组。抑肽酶减少斑块中组织蛋白酶的表达和激活，阻断 PAR-2 和 MMP-9 的激活，减少细胞因子的表达；还增加纤维帽厚度，减少内膜-中膜厚度和内膜/中膜比值，从而显著改善斑块易损性。在接受冠状动脉旁路移植术的患者的冠状动脉内膜粥样硬化斑块中也发现上调的组织蛋白酶、MMP-9 和 PAR-2。
在动脉粥样硬化斑块中，组织蛋白酶明显上调，通过激活 PAR-2 增加促炎细胞因子水平，并通过激活 proMMP-9 促进斑块不稳定，从而促进动脉粥样硬化和斑块易损性。此外，人冠状动脉内膜粥样硬化斑块中高表达的组织蛋白酶提示，靶向组织蛋白酶可能是预防急性冠状动脉综合征的新策略。
