活性金属基质蛋白酶-9的表达增高可能导致脑动静脉畸形出血风险增加的研究

摘要/Abstract

摘要：

【摘要】目的探讨金属基质蛋白酶-9（matrix metalloproteinase-9，MMP-9）在脑动静脉畸形出血机制中的作用。方法收集2010年10月至2011年3月天坛医院住院的脑动静脉畸形（arteriovenous malformation，AVM）患者及颞叶癫痫患者。根据手术切下的动静脉畸形的血管巢及癫痫手术患者术中切除的脑组织，分为脑动静脉畸形出血组（14例）、未出血组（17例）和对照组（25例）。采用Western蛋白印迹检测组织中MMP-9蛋白水平的表达。采用免疫荧光方法检测各组MMP-9的表达，明胶酶谱检测组织中有活性的MMP-2和MMP-9蛋白的表达。结果 MMP-9蛋白在未出血组中表达高于对照组和出血组（1.21±0.34 vs 0.35±0.06，P =0.0014；1.21±0.34 vs 0.32±0.08，P =0.047），出血组和对照组之间差异无显著性（0.32±0.08 vs0.35±0.06，P =0.7456）。显示MMP-9蛋白的活性明胶酶谱中，出血组和未出血组及对照组之间的差异有显著性（0.97±0.08 vs 0.40±0.09，P =0.009；0.97±0.08 vs 0.30±0.07，P =0.0034）。在出血组，有活性的MMP-2的表达同样高于未出血组和对照组，差异有显著性（1.36±0.17 vs 0.55±0.12，P =0.019；1.36±0.17 vs 0.36±0.09，P =0.006）。结论在脑动静脉畸形组织中活性MMP-9表达增高，在破裂出血的动静脉畸形中MMP-9更多转化为活性的形式出现。

关键词: 金属基质蛋白酶-9; 脑动静脉畸形; 脑出血

Abstract:

【Abstract】 Objective To investigate the role of MMP-9 in the hemorrhagic mechanism of cerebral arteriovenous malformation(AVM).

Methods Thirty-one patients with AVMs and 25 patients with epilepsy were admitted in our hospital during October 2010 to March 2011. The AVM tissue samples were divided into a ruptured group, non-ruptured group and control group. Tissue samples were obtained from the AVM nidus during surgery or from the temporal lobectomy of patients undergoing surgical treatment of epilepsy. Western blot analysis was used to measure MMP-9 in the tissues. Immunofluorescence was used to measure tissue MMP-9 expression in each group. Gelatin zymography showed the expression of activated MMP-2 and MMP-9 in the tissue.

Results MMP-9 protein expression in the non-ruptured group was greater than that in the normal group and the ruptured group. (1.21±0.34 vs 0.35±0.06, P =0.0014; 1.21±0.34 vs 0.32±0.08,P =0.047), but no difference between the ruptured and the control group(0.32±0.08 vs 0.35±0.06,P =0.7456). Gelatin zymography showed that the activity of MMP-9 was significantly higher in the ruptured than the non-ruptured and control groups(0.97±0.08 vs 0.40±0.09, P =0.009; 0.97±0.08 vs 0.30±0.07, P =0.0034). In the ruptured group, active MMP-2 expression was significantly higher than that in the unruptured and control group(1.36±0.17 vs 0.55±0.12, P =0.019; 1.36±0.17 vs 0.36±0.09, P =0.006).

Conclusion MMP-9 had higher expression in the AVM tissues and more MMP-9 transformed to activated form in ruptured AVM tissues; this may lead to increase in hemorrhage risk due to AVM.

Key words: Matrix metalloproteinase-9; Cerebral arteriovenous malformation; Hemorrhage

李雄，王嵘，刘泠，吴俊，彭磊，李宇，王硕. 活性金属基质蛋白酶-9的表达增高可能导致脑动静脉畸形出血风险增加的研究[J]. 卒中杂志, 2012, 7(11): 845-849.

LI Xiong*, WANG Rong, LIU Ling, WU Jun,PENG Lei, LI Yu, WANG Shuo.. Study on High Level Expression of Activated MMP-9 may Increase Hemorrhagic Risk of Cerebral Arteriovenous Malformation[J]. Chinese Journal of Stroke, 2012, 7(11): 845-849.

参考文献

1 ApSimon HT, Reef H, Phadke RV, et al. A populationbased study of brain arteriovenous malformation:longterm treatment outcomes[J]. Stroke, 2002, 33:2794-2800.

2 Crawford PM, West CR, Chadwick DW, et al.Arteriovenous malformations of the brain:natural history in unoperated patients[J]. J Neurol Neurosurg Psychiatry, 1986, 49:1-10.

3 Fults D, Kelly DL Jr. Natural history of arteriovenous malformations of the brain:a clinical study[J].Neurosurgery, 1984, 15:658-662.

4 Ma r t i n NA. Tr e a t me n t o f a r t e r i o v e n o u s malformations:indications, grading, and techniques[J].J Stroke Cerebrovasc Dis, 1997, 6:272-276.

5 Ak soy Y, Er c a n A, Da lmi z r a k O, e t a l. The determination of matrixmetalloproteinase 9 activity and gene expression levels in Behcet's disease patients with aneurysmal complications[J]. Clin Rheumatol,2011, 30:515-519.

6 Loftus IM, Naylor AR, Goodall S, et al. Increased matrix metalloproteinase-9 activity in unstable carotid plaques:a potential role in acute plaque disruption[J].Stroke, 2000, 31:40-47.

7 Chyatte D, Lewis I. Gelatinase activity and the occurrence of cerebral aneurysms[J]. Stroke, 1997,28:799-804.

8 Hashimoto T, Lawton MT, Wen G, et al. Gene microarray analysis of human brain arteriovenous malformations[J]. Neurosurgery, 2004, 54:410-425.

9 钟春龙, 马其中, 王勇, 等. 脑动静脉畸形出血危险因素的分析与评价[J]. 上海医学, 1998, 21:376-378.

10 孙异临, 王忠诚, 曲宝清, 等. 脑动静脉畸形超微病理与临床症状的关系[J]. 北京医学, 1997, 19:3-6.

11 Hashimoto T, Wu Y, Lawton MT, et al. Co-expression of angiogenic fa ctor s in br ain a r t e r iovenous malformations[J]. Neurosurgery, 2005, 56:1058-1065.

12 Chen Y, Zhu W, Bollen AW, et al. Evidence of inflammatory cell involvement in brain arteriovenous malformations[J]. Neurosurgery, 2008, 62:1340-1350.

13 Fishman D, Faulds G, Jeffery R, et al. The effect of novel polymorphisms in the interleukin-6(IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association ith systemiconset juvenile chronicarthritis[J]. J Clin Invest, 1998, 102:1369-1376.

14 邸飞, 李洪利, 赵继宗, 等. 基质金属蛋白酶-9及组织基质金属蛋白酶抑制剂-1在脑动静脉畸形组织中的表达及其与出血的关系[J]. 中国卒中杂志, 2009, 7:576-580.

15 Starke RM, Komotar RJ, Hwang BY, et al. Systemic expression of matrix metallo proteinase-9 in patients with cerebral ar ter iovenous malformations[J].Neurosurgery, 2010, 66:343-348.

16 S t e r n l i c h t M D , We r b Z . H o w m a t r i x metalloproteinases regulate cell behavior[J]. Annu Rev Cell Dev Biol, 2001, 17:463-516.

17 Kr ishnamur thy VK, Opoka AM, Ker n CB, et al. Maladaptive matrix remodeling and regional biomechanical dysfunction in a mouse model of aortic valve disease[J]. Matrix Biol, 012, 31:197-205.

18 Br i n c k e r h o f f C E , Ma t r i s i a n LM. Ma t r i x metalloproteinases:a tail of a frog that became a prince[J]. Nat Rev Mol Cell Biol, 2002, 3:207-214.

[1]	郑占军, 赵性泉. 脑小血管病影像学标志物与自发性高血压脑出血的相关性研究进展[J]. 中国卒中杂志, 2022, 17(12): 1396-1402.
[2]	程实, 李静, 郭军平, 胡爱香, 于鑫玮, 韩玮, 梁瑛, 张越巍, 冀瑞俊. 急性卒中患者住院期间感染的临床特征及危险因素分析[J]. 中国卒中杂志, 2022, 17(10): 1065-1070.
[3]	范琳琳, 田飞. 以癫痫持续状态和脑出血为特征的胶质母细胞瘤1例并文献复习[J]. 中国卒中杂志, 2022, 17(09): 1002-1006.
[4]	王拥军, 李子孝, 谷鸿秋, 翟屹, 姜勇, 周齐, 赵性泉, 王伊龙, 杨昕, 王春娟, 孟霞, 李昊, 刘丽萍, 荆京, 吴静, 徐安定, 董强, David Wang, 王文志, 马旭东, 赵继宗, 《中国卒中报告》编写委员会（第一作者）. 中国卒中报告2020（中文版）（3）[J]. 中国卒中杂志, 2022, 17(07): 675-682.
[5]	宋新杰, 姜睿璇, 张怡君, 王安心, 李子孝, 赵性泉. 脑出血急性期不同血压参数与预后的关系[J]. 中国卒中杂志, 2022, 17(07): 769-773.
[6]	王拥军, 李子孝, 谷鸿秋, 翟屹, 姜勇, 周齐, 赵性泉, 王伊龙, 杨昕, 王春娟, 孟霞, 李昊, 刘丽萍, 荆京, 吴静, 徐安定, 董强, David Wang, 王文志, 马旭东, 赵继宗, 《中国卒中报告》编写委员会（第一作者）. 中国卒中报告2020（中文版）（2）[J]. 中国卒中杂志, 2022, 17(06): 553-567.
[7]	李昊, 许宏远, 押小龙, 曹勇. 散发性脑动静脉畸形KRAS突变及其与临床特征的关系[J]. 中国卒中杂志, 2022, 17(06): 611-615.
[8]	宋新杰, 王安心, 李子孝, 赵性泉. 下肢深静脉血栓形成与脑出血患者预后的关系研究[J]. 中国卒中杂志, 2022, 17(06): 634-637.
[9]	王拥军, 李子孝, 谷鸿秋, 翟屹, 姜勇, 周齐, 赵性泉, 王伊龙, 杨昕, 王春娟, 孟霞, 李昊, 刘丽萍, 荆京, 吴静, 徐安定, 董强, David Wang, 王文志, 马旭东, 赵继宗, 《中国卒中报告》编写委员会（第一作者）. 中国卒中报告2020（中文版）（1）[J]. 中国卒中杂志, 2022, 17(05): 433-447.
[10]	刘欣瑶, 毕京凤, 张英魁. 脑出血信号改变机制与磁共振影像表现[J]. 中国卒中杂志, 2021, 16(12): 1217-1221.
[11]	冯皓, 王鑫, 王文娟, 赵性泉. 不同性别老年脑出血患者血脂水平与预后的关系研究[J]. 中国卒中杂志, 2021, 16(10): 1016-1022.
[12]	陈晴晴, 孙金菊, 周雪姣. 急性脑出血继发院内消化道出血的影响因素分析[J]. 中国卒中杂志, 2021, 16(10): 1029-1033.
[13]	徐昳, 陈淑芬, 韩翔. 感染性心内膜炎合并脑出血伴多器官梗死1例[J]. 中国卒中杂志, 2021, 16(08): 774-778.
[14]	王丹丹, 王晶, 王安心, 张怡君, 赵性泉. 超敏C反应蛋白与新发脑出血关系研究[J]. 中国卒中杂志, 2021, 16(07): 664-669.
[15]	王振, 徐伟, 贺国华, 胡珏, 冯铁桥, 童洋萍, 徐桂兰, 肖慧, 易海波, 宋治. 急性缺血性卒中静脉溶栓后远隔部位脑出血的临床特征和预后分析[J]. 中国卒中杂志, 2021, 16(07): 680-686.