基质金属蛋白酶及其基因多态性在缺血性卒中病理过程中的作用

doi:10.3969/j.issn.1673-5765.2019.05.020

摘要/Abstract

摘要：

基质金属蛋白酶9（matrix metalloproteinases 9，MMP9）被证明在缺血性卒中患者梗死灶及梗死灶周围脑组织，梗死灶血管周围及外周血中性粒细胞中均高表达。聚合酶δ-相互作用蛋白2、白细胞介素17（interleukin17，IL-17）、肿瘤坏死因子α、IL-1β、心血管活性肽、血管内皮生长因子等可通过p38丝裂原活化蛋白激酶（mitogen activated protein kinases，MAPK）、细胞外调节蛋白激酶1/2依赖的核因子κB（nuclear factor κB，NF-κB）和活化蛋白-1、p42/p44MAPK、c-Jun氨基末端激酶、p65- NF-κB等不同途径促进MMP9的表达。MMP9的高表达与缺血性卒中出血转化关系密切，且外周血 MMP9水平变化与rt-PA溶栓患者死亡或症状性颅内出血独立相关，与缺血性卒中严重程度及不良功能结局相关。MMP9 rs3918242位点基因多态性与缺血性卒中的风险及疾病严重程度可能相关，但目前研究的结果和结论尚不一致。

文章导读： 本文对基质金属蛋白酶9在缺血性卒中后的激活，参与脑损伤的可能机制，其基因多态性与卒中及卒中后出血转化的关系研究进行了总结。

关键词: 卒中; 基质金属蛋白酶9; 基因多态性; 出血转化

Abstract:

When ischemic stroke occurs, matrix metalloproteinases 9 (MMP9) has been shown to be highly expressed in infarct lesion and surrounding cerebral tissue, and neutrophils will be highly expressed in perivascular around infarct focus and peripheral blood. Polymerase δ-interacting protein 2, interleukin17 (IL-17), tumor necrosis factor alpha, IL-1β, cardiovascular active peptide, vascular endothelial growth factor may promote the expression of MMP9 through p38 mitogen activated protein kinases (MAPK), extracellular regulated protein kinases 1/2-dependent nuclear factor κB (NF-κB) and activated protein 1, p42/p44MAPK, c-Jun N-terminal kinase, p65-NF-κB and other pathways. The high expression of MMP 9 is closely related to hemorrhagic transformation in ischemic stroke. The MMP9 level in peripheral blood is closely correlated with ischemic stroke severity, and is an independent risk factor for death and symptomatic intracranial hemorrhage in patients with rt-PA thrombolysis, and related to poor outcome of ischemic stroke patients. The gene locus polymorphism of MMP9 rs3918242 may be associated with the risk of ischemic stroke and the disease severity, but current research results are still inconsistent.

Key words: Stroke; Matrix metallopeptidase 9; Polymorphism; Hemorrhagic transformation

张敏，马丽，赵咏梅，吕燕敏，龙会登，庞丽娟. 基质金属蛋白酶及其基因多态性在缺血性卒中病理过程中的作用[J]. 中国卒中杂志, 2019, 14(05): 504-510.

ZHANG Min, MA Li, ZHAO Yong-Mei, LYU Yan-Min, LONG Hui-Deng, PANG Li-Juan. Progress in Pathophysiological Mechanism of Matrix Metalloproteinases 9 and its Gene Polymorphism in Ischemic Cerebral Injury[J]. Chinese Journal of Stroke, 2019, 14(05): 504-510.

参考文献

[1] MUN-BRYCE S，ROSENBERG G A. Matrix

metalloproteinases in cerebrovascular disease[J]. J

Cereb Blood Flow Metab，1998，18（11）：1163-1172.

[2] SIMAO F，USTUNKAYA T，CLERMONT A C，et

al. Plasma kallikrein mediates brain hemorrhage

and edema caused by tissue plasminogen activator

therapy in mice after stroke[J]. Blood，2017，129

（16）：2280-2290.

[3] ROSENBERG G A，NAVRATIL M，BARONE

F，et al. Proteolytic cascade enzymes increase in

focal cerebral ischemia in rat[J]. J Cereb Blood Flow

Metab，1996，16（3）：360-366.

[4] MAIER C M，HSIEH L，YU F，et al. Matrix

metalloproteinase-9 and myeloperoxidase

expression：quantitative analysis by antigen

immunohistochemistry in a model of transient focal

cerebral ischemia[J]. Stroke，2004，35（5）：1169-

1174.

[5] ROMANIC A M，WHITE R F，ARLETH A J，et al.

Matrix metalloproteinase expression increases after

cerebral focal ischemia in rats：inhibition of matrix

metalloproteinase-9 reduces infarct size[J]. Stroke，

1998，29（5）：1020-1030.

[6] ZHAO B Q，WANG S，KIM H Y，et al. Role of matrix metalloproteinases in delayed cortical

responses after stroke[J]. Nature medicine，2006，12

（4）：441-445.

[7] GIDDAY J M，GASCHE Y G，COPIN J C，et al.

Leukocyte-derived matrix metalloproteinase-9

mediates blood-brain barrier breakdown and is

proinflammatory after transient focal cerebral

ischemia[J]. Am J Physiol Heart Circ Physiol，2005，

289（2）：H558-H568.

[8] BORREGAARD N，COWLAND J B. Granules

of the human neutrophilic polymorphonuclear

leukocyte[J]. Blood，1997，89（10）：3503-3521.

[9] HIBBS M S，HASTY K A，SEYER J M，et al.

Biochemical and immunological characterization of

the secreted forms of human neutrophil gelatinase[J].

J Biol Chem，1985，260（4）：2493-500.

[10] OPDENAKKER G，VAN DEN STEEN P E，

DUBOIS B，et al. Gelatinase B functions as regulator

and effector in leukocyte biology[J]. J Leukoc Biol，

2001，69（6）：851-859.

[11] ROSELL A，ORTEGA-AZNAR A，ALVAREZSABIN

J，et al. Increased brain expression of matrix

metalloproteinase-9 after ischemic and hemorrhagic

human stroke[J]. Stroke，2006，37（6）：1399-1406.

[12] ANTHONY D C，FERGUSON B，MATYZAK

M K，et al. Differential matrix metalloproteinase

expression in cases of multiple sclerosis and

stroke[J]. Neuropathol Appl Neurobiol，1997，23（5）：

406-415.

[13] REYNOLDS M A，KIRCHICK H J，DAHLEN J

R，et al. Early Biomarkers of Stroke[J]. Clin Chem，

2003，49（10）：1733-1739.

[14] HORSTMANN S，KALB P，KOZIOL J，et al.

Profiles of matrix metalloproteinases，their inhibitors，

and laminin in stroke patients：influence of different

therapies[J]. Stroke，2003，34（9）：2165-2170.

[15] CASTELLANOS M，LEIRA R，SERENA J，et al.

Plasma metalloproteinase-9 concentration predicts

hemorrhagic transformation in acute ischemic

stroke[J]. Stroke，2003，34（1）：40-46.

[16] ROSELL A，ALVAREZ-SABIN J，ARENILLAS

J F，et al. A matrix metalloproteinase protein array

reveals a strong relation between MMP-9 and MMP-

13 with diffusion-weighted image lesion increase in

human stroke[J]. Stroke，2005，36（7）：1415-1420.

[17] KAPLAN R C，SMITH N L，ZUCKER S，et al.

Matrix metalloproteinase-3（MMP3）and MMP9

genes and risk of myocardial infarction，ischemic

stroke，and hemorrhagic stroke[J]. Atherosclerosis，

2008，201（1）：130-137.

[18] BUSTAMANTE A，LOPEZ-CANCIO E，PICH

S，et al. Blood biomarkers for the early diagnosis

of stroke：the stroke-chip study[J]. Stroke，2017，48

（9）：2419-2425.

[19] GU Z，KAUL M，YAN B，et al. S-nitrosylation of

matrix metalloproteinases：signaling pathway to

neuronal cell death[J]. Science，2002，297（5584）：

1186-1190.

[20] HERNANDES M S，LASSEGUE B，HILENSKI

L L，et al. Polymerase delta-interacting protein

2 deficiency protects against blood-brain

barrier permeability in the ischemic brain[J]. J

Neuroinflammation，2018，15（1）：45.

[21] CHENG G，WEI L，XIURONG W，et al. IL-

17 stimulates migration of carotid artery vascular

smooth muscle cells in an MMP-9 dependent manner

via p38 MAPK and ERK1/2-dependent NF-kappaB

and AP-1 activation[J]. Cell Mol Neurobiol，2009，29

（8）：1161-1168.

[22] MOON S K，CHA B Y，KIM C H. ERK1/2 mediates

TNF-alpha-induced matrix metalloproteinase-9

expression in human vascular smooth muscle

cells via the regulation of NF-kappaB and AP-1：

involvement of the ras dependent pathway[J]. J Cell

Physiol，，2004，198（3）：417-427.

[23] LIANG K，LEE C，LIN W，et al. Interleukin-1β

induces MMP-9 expression via p42/p44 MAPK，

p38 MAPK，JNK，and nuclear factor-κB signaling

pathways in human tracheal smooth muscle cells[J].

J Cell Physiol，2007，211（3）：759-770.

[24] SUN H J，ZHAO M X，REN X S，et al. Salusin-beta

promotes vascular smooth muscle cell migration and

intimal hyperplasia after vascular injury via ROS/

NFkappaB/MMP-9 pathway[J]. Antioxid Redox

Signal，2016，24（18）：1045-1057.

[25] HOLLBORN M，STATHOPOULOS C，STEFFEN

A，et al. Positive feedback regulation between

MMP-9 and VEGF in human RPE cells[J]. nvest

Ophthalmol Vis Sci，2007，48（9）：4360-4367.

[26] BELL R D，WINKLER E A，SINGH I，et al.

Apolipoprotein E controls cerebrovascular integrity

via cyclophilin A[J]. Nature，2012，485（7399）：512-

516.

[27] MONTANER J，ALVAREZ-SABíN J，MOLINA C，

et al. Matrix metalloproteinase expression is related

to hemorrhagic transformation after cardioembolic

stroke[J]. Stroke，2001，32（12）：2762-2767.

[28] MONTANER J，FERNã N-C I，MOLINA C A，et

al. Safety profile of tissue plasminogen activator

treatment among stroke patients carrying a common

polymorphism（C-1562T）in the promoter region of

the matrix metalloproteinase-9 gene[J]. Stroke，2003，34（12）：2851-2855.

[29] CASTELLANOS M，SOBRINO T，MILLAN

M，et al. Serum cellular fibronectin and matrix

metalloproteinase-9 as screening biomarkers for

the prediction of parenchymal hematoma after

thrombolytic therapy in acute ischemic stroke：a

multicenter confirmatory study[J]. Stroke，2007，38

（6）：1855-1859.

[30] WANG X，LEE S-R，ARAI K，et al. Lipoprotein

receptor-mediated induction of matrix

metalloproteinase by tissue plasminogen activator[J].

Nat Med，2003，9（10）1313-1317.

[31] HU K，YANG J，TANAKA S，et al. Tissue-type

plasminogen activator acts as a cytokine that triggers

intracellular signal transduction and induces matrix

metalloproteinase-9 gene expression[J]. J Biol Chem，

2006，281（4）：2120-2127.

[32] INZITARI D，GIUSTI B，NENCINI P，et al. MMP9

variation after thrombolysis is associated with

hemorrhagic transformation of lesion and death[J].

Stroke，2013，44（10）：2901-2903.

[33] MONTRUCCHIO G，LUPIA E，DE MARTINO A，

et al. Plasmin promotes an endothelium-dependent

adhesion of neutrophils. Involvement of platelet

activating factor and P-selectin[J]. Circulation，1996，

93（12）：2152-2160.

[34] HAO Y，TIAN S，SUN M，et al. Association

between matrix metalloproteinase gene

polymorphisms and development of ischemic

stroke[J]. Int J Clin Exp Pathol，2015，8（9）：11 647-

11 652.

[35] LI Y，CHEN L，YAO S，et al. Association of

polymorphisms of the matrix metalloproteinase 9

gene with ischaemic stroke in a southern Chinese

population[J]. Cell Physiol Biochem，2018，49（6）：

2188-2199.

[36] BURACZYNSKA K，KURZEPA J，KSIAZEK A，

et al. Matrix metalloproteinase-9（MMP-9）gene

polymorphism in stroke patients[J]. Neuromolecular

med，2015，17（4）：385-390.

[37] HE T，WANG J，WANG X L，et al. Association

between the matrix metalloproteinase-9 rs3918242

polymorphism and ischemic stroke susceptibility：a

meta-analysis[J]. J Stroke Cerebrovasc Dis，2017，26

（5）：1136-1143.

[38] WANG B，WANG Y，ZHAO L. MMP-9 gene

rs3918242 polymorphism increases risk of stroke：a

meta-analysis[J]. J Cell Biochem，2018，119（12）：

9801-9808.

[39] KATAKAMI N，TAKAHARA M，KANETO H，et

al. Accumulation of gene polymorphisms related

to plaque disruption and thrombosis is associated

with cerebral infarction in subjects with type 2

diabetes[J]. Diabetes care，2010，33（2）：390-395.

[40] FERNANDEZ-CADENAS I，DEL RIO-ESPINOLA

A，CARRERA C，et al. Role of the MMP9 gene

in hemorrhagic transformations after tissue-type

plasminogen activator treatment in stroke patients[J].

Stroke，2012，43（5）：1398-1400.

[41] BARR T L，LATOUR L L，LEE K Y，et al. Bloodbrain

barrier disruption in humans is independently

associated with increased matrix metalloproteinase-

9[J/OL]. Stroke，2010，41（3）：e123-e128. https：//

doi.org/10.1161/STROKEAHA.109.570515.

[42] CHEON S Y，KIM S Y，KAM E H，et al. Isoflurane

preconditioning inhibits the effects of tissue-type

plasminogen activator on brain endothelial cell in an

in vitro model of ischemic stroke[J]. Int J Med Sci，

2017，14（5）：425-433.

[43] WANG T H，XIONG L L，YANG S F，et al. LPS

pretreatment provides neuroprotective roles in rats

with subarachnoid hemorrhage by downregulating

MMP9 and caspase3 associated with TLR4 signaling

activation[J]. Mol Neurobio，2017，54（10）：7746-

7760.

[44] SUDA S，YANG B，SCHAAR K，et al. Autologous

bone marrow mononuclear cells exert broad

effects on short- and long-term biological and

functional outcomes in rodents with intracerebral

hemorrhage[J]. Stem Cells Dev，2015，24（23）：

2756-2766.