TIMP-2 Polymorphisms Define Subtypes of Hypertensive Intracerebral Hemorrhage with Distinct Perihematomal Edema Development Patterns

Author(s): Ru Chen, Zhi Song*, Mingzhu Deng, Wen Zheng, Jia Liu, Lihua Huang

Journal Name: Current Neurovascular Research

Volume 17 , Issue 1 , 2020

Become EABM
Become Reviewer
Call for Editor


Background: Perihematomal edema (PHE) is a major threat leading to poor functional outcomes after intracerebral hemorrhage (ICH). TIMP-2 is considered to participate in the formation of PHE after ICH by antagonizing the damaging effects of MMP-2. In the early study, the polymorphisms of TIMP-2 rs8179090 have shown to influence the expression of TIMP-2.

Objective: To prove that the severity of PHE was different in ICH patients with different TIMP-2 rs8179090 genotypes.

Methods: In this prospective study, 130 hypertensive ICH patients were enrolled. The poly phisms of rs8179090 in TIMP-2 were determined. The hematoma volume and PHE volume were measured by computed tomography (CT) scan immediately after the onset of ICH, and were measured again one week and two weeks after the onset. Then, the comparison of TIMP-2 rs8179090 genotypes was made.

Results: TIMP-2-418 position (rs8179090) had two genotypes in the studied population, GC and GG. Patients with the GC genotype developed more severe PHE, with a higher incidence of delayed cerebral edema in cerebral hemorrhage than those with the GG genotype.

Conclusion: We have found that the GC genotype group may develop more severe PHE, with an increased incidence of delayed cerebral edema in cerebral hemorrhage.

Keywords: Hypertensive intracerebral hemorrhage, perihematomal edema, polymorphism, TIMP-2, blood brain barrier, outcome.

Elliott, J.; Smith, M. The acute management of intracerebral hemorrhage: A clinical review. Anesth. Analg., 2010, 110(5), 1419-1427.
[http://dx.doi.org/10.1213/ANE.0b013e3181d568c8] [PMID: 20332192]
Qureshi, A.I.; Mendelow, A.D.; Hanley, D.F. Intracerebral haemorrhage. Lancet, 2009, 373(9675), 1632-1644.
[http://dx.doi.org/10.1016/S0140-6736(09)60371-8] [PMID: 19427958]
Murthy, S.B.; Moradiya, Y.; Dawson, J. VISTA-ICH Collaborators. Perihematomal edema and functional outcomes in intracerebral hemorrhage: Influence of hematoma volume and location. Stroke, 2015, 46(11), 3088-3092.
[http://dx.doi.org/10.1161/STROKEAHA.115.010054] [PMID: 26396030]
John, R.F.; Colbourne, F. Delayed localized hypothermia reduces intracranial pressure following collagenase-induced intracerebral hemorrhage in rat. Brain Res., 2016, 1633, 27-36.
[http://dx.doi.org/10.1016/j.brainres.2015.12.033] [PMID: 26723566]
Urday, S.; Beslow, L.A.; Goldstein, D.W. Measurement of perihematomal edema in intracerebral hemorrhage. Stroke, 2015, 46(4), 1116-1119.
[http://dx.doi.org/10.1161/STROKEAHA.114.007565] [PMID: 25721012]
Yang, J.; Arima, H.; Wu, G. INTERACT Investigators. Prognostic significance of perihematomal edema in acute intracerebral hemorrhage: pooled analysis from the intensive blood pressure reduction in acute cerebral hemorrhage trial studies. Stroke, 2015, 46(4), 1009-1013.
[http://dx.doi.org/10.1161/STROKEAHA.114.007154] [PMID: 25712944]
Leasure, A.; Kimberly, W.T.; Sansing, L.H. Treatment of edema associated with intracerebral hemorrhage. Curr. Treat. Options Neurol., 2016, 18(2), 9.
[http://dx.doi.org/10.1007/s11940-015-0392-z] [PMID: 26874842]
Zazulia, A.R.; Diringer, M.N.; Derdeyn, C.P.; Powers, W.J. Progression of mass effect after intracerebral hemorrhage. Stroke, 1999, 30(6), 1167-1173.
[http://dx.doi.org/10.1161/01.STR.30.6.1167] [PMID: 10356094]
Rosell, A.; Lo, E.H. Multiphasic roles for matrix metalloproteinases after stroke. Curr. Opin. Pharmacol., 2008, 8(1), 82-89.
[http://dx.doi.org/10.1016/j.coph.2007.12.001] [PMID: 18226583]
Nagase, H.; Visse, R.; Murphy, G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc. Res., 2006, 69(3), 562-573.
[http://dx.doi.org/10.1016/j.cardiores.2005.12.002] [PMID: 16405877]
Candelario-Jalil, E.; Yang, Y.; Rosenberg, G.A. Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia. Neuroscience, 2009, 158(3), 983-994.
[http://dx.doi.org/10.1016/j.neuroscience.2008.06.025] [PMID: 18621108]
Lee, E.J.; Ko, H.M.; Jeong, Y.H.; Park, E.M.; Kim, H.S. β-Lapachone suppresses neuroinflammation by modulating the expression of cytokines and matrix metalloproteinases in activated microglia. J. Neuroinflammation, 2015, 12, 133.
[http://dx.doi.org/10.1186/s12974-015-0355-z] [PMID: 26173397]
Yang, Y.; Estrada, E.Y.; Thompson, J.F.; Liu, W.; Rosenberg, G.A. Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J. Cereb. Blood Flow Metab., 2007, 27(4), 697-709.
[http://dx.doi.org/10.1038/sj.jcbfm.9600375] [PMID: 16850029]
Power, C.; Henry, S.; Del Bigio, M.R. Intracerebral hemorrhage induces macrophage activation and matrix metalloproteinases. Ann. Neurol., 2003, 53(6), 731-742.
[http://dx.doi.org/10.1002/ana.10553] [PMID: 12783419]
Chang, J.J.; Emanuel, B.A.; Mack, W.J.; Tsivgoulis, G.; Alexandrov, A.V. Matrix metalloproteinase-9: Dual role and temporal profile in intracerebral hemorrhage. J. Stroke Cerebrovasc. Dis., 2014, 23(10), 2498-2505.
[http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.07.005] [PMID: 25306400]
Rosenberg, G.A.; Navratil, M. Metalloproteinase inhibition blocks edema in intracerebral hemorrhage in the rat. Neurology, 1997, 48(4), 921-926.
[http://dx.doi.org/10.1212/WNL.48.4.921] [PMID: 9109878]
Wu, H.; Wu, T.; Hua, W. PGE2 receptor agonist misoprostol protects brain against intracerebral hemorrhage in mice. Neurobiol. Aging, 2015, 36(3), 1439-1450.
[http://dx.doi.org/10.1016/j.neurobiolaging.2014.12.029] [PMID: 25623334]
Li, Y.Y.; Feldman, A.M.; Sun, Y.; McTiernan, C.F. Differential expression of tissue inhibitors of metalloproteinases in the failing human heart. Circulation, 1998, 98(17), 1728-1734.
[http://dx.doi.org/10.1161/01.CIR.98.17.1728] [PMID: 9788826]
de Souza, A.P.; Trevilatto, P.C.; Scarel-Caminaga, R.M.; de Brito, R.B., Jr; Barros, S.P.; Line, S.R. Analysis of the MMP-9 (C-1562 T) and TIMP-2 (G-418C) gene promoter polymorphisms in patients with chronic periodontitis. J. Clin. Periodontol., 2005, 32(2), 207-211.
[http://dx.doi.org/10.1111/j.1600-051X.2005.00665.x] [PMID: 15691353]
De Clerck, Y.A.; Darville, M.I.; Eeckhout, Y.; Rousseau, G.G. Characterization of the promoter of the gene encoding human tissue inhibitor of metalloproteinases-2 (TIMP-2). Gene, 1994, 139(2), 185-191.
[http://dx.doi.org/10.1016/0378-1119(94)90753-6] [PMID: 8112602]
Park, Y.S.; Jeon, Y.J.; Kim, H.S. The GC+CC genotype at position -418 in TIMP-2 promoter and the -1575GA/-1306CC genotype in MMP-2 is genetic predisposing factors for prevalence of moyamoya disease. BMC Neurol., 2014, 14, 180.
[http://dx.doi.org/10.1186/s12883-014-0180-5] [PMID: 25280484]
Coven, İ.; Ozer, O.; Ozen, O.; Şahin, F.I.; Altinors, N. Presence of matrix metalloproteinase-2 and tissue inhibitor matrix metalloproteinase-2 gene polymorphisms and immunohistochemical expressions in intracranial meningiomas. J. Neurosurg., 2014, 121(6), 1478-1482.
[http://dx.doi.org/10.3171/2014.8.JNS13515] [PMID: 25259564]
Mikołajczyk-Stecyna, J.; Korcz, A.; Gabriel, M.; Pawlaczyk, K.; Oszkinis, G.; Słomski, R. Gene polymorphism -418 G/C of tissue inhibitor of metalloproteinases 2 is associated with abdominal aortic aneurysm. J. Vasc. Surg., 2015, 61(5), 1114-1119.
[http://dx.doi.org/10.1016/j.jvs.2013.12.045] [PMID: 24534323]
Hemphill, J.C., III; Greenberg, S.M.; Anderson, C.S. American Heart Association Stroke Council. Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology. Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: A guideline for healthcare professionals from the American heart association/American stroke association. Stroke, 2015, 46(7), 2032-2060.
[http://dx.doi.org/10.1161/STR.0000000000000069] [PMID: 26022637]
Ducruet, A.F.; Hickman, Z.L.; Zacharia, B.E. Exacerbation of perihematomal edema and sterile meningitis with intraventricular administration of tissue plasminogen activator in patients with intracerebral hemorrhage. Neurosurgery, 2010, 66(4), 648-655.
[http://dx.doi.org/10.1227/01.NEU.0000360374.59435.60] [PMID: 20305489]
Naval, N.S.; Abdelhak, T.A.; Urrunaga, N.; Zeballos, P.; Mirski, M.A.; Carhuapoma, J.R. An association of prior statin use with decreased perihematomal edema. Neurocrit. Care, 2008, 8(1), 13-18.
[http://dx.doi.org/10.1007/s12028-007-0081-1] [PMID: 17701107]
Rosenberg, G.A. Matrix metalloproteinases in neuroinflammation. Glia, 2002, 39(3), 279-291.
[http://dx.doi.org/10.1002/glia.10108] [PMID: 12203394]
Gebel, J.M., Jr; Jauch, E.C.; Brott, T.G. Relative edema volume is a predictor of outcome in patients with hyperacute spontaneous intracerebral hemorrhage. Stroke, 2002, 33(11), 2636-2641.
[http://dx.doi.org/10.1161/01.STR.0000035283.34109.EA] [PMID: 12411654]
Alp, E.; Yilmaz, A.; Tulmac, M. Analysis of MMP-7 and TIMP-2 gene polymorphisms in coronary artery disease and myocardial infarction: A Turkish case-control study. Kaohsiung J. Med. Sci., 2017, 33(2), 78-85.
[http://dx.doi.org/10.1016/j.kjms.2016.12.002] [PMID: 28137415]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 23 December, 2019
Page: [44 - 49]
Pages: 6
DOI: 10.2174/1567202617666191223145632
Price: $65

Article Metrics

PDF: 18
PRC: 2