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Review

The Role of Matrix Metalloproteinase Polymorphisms in Ischemic Stroke

by
Jason J. Chang
1,*,
Ansley Stanfill
2 and
Tayebeh Pourmotabbed
3
1
Department of Neurology, University of Tennessee Health Science Center, Memphis, TN 38104, USA
2
Department of Nursing and Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38104, USA
3
Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38104, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2016, 17(8), 1323; https://doi.org/10.3390/ijms17081323
Submission received: 23 June 2016 / Revised: 22 July 2016 / Accepted: 26 July 2016 / Published: 12 August 2016
(This article belongs to the Special Issue Metalloproteins)
Versions Notes

Abstract

:
Stroke remains the fifth leading cause of mortality in the United States with an annual rate of over 128,000 deaths per year. Differences in incidence, pathogenesis, and clinical outcome have long been noted when comparing ischemic stroke among different ethnicities. The observation that racial disparities exist in clinical outcomes after stroke has resulted in genetic studies focusing on specific polymorphisms. Some studies have focused on matrix metalloproteinases (MMPs). MMPs are a ubiquitous group of proteins with extensive roles that include extracellular matrix remodeling and blood-brain barrier disruption. MMPs play an important role in ischemic stroke pathophysiology and clinical outcome. This review will evaluate the evidence for associations between polymorphisms in MMP-1, 2, 3, 9, and 12 with ischemic stroke incidence, pathophysiology, and clinical outcome. The role of polymorphisms in MMP genes may influence the presentation of ischemic stroke and be influenced by racial and ethnic background. However, contradictory evidence for the role of MMP polymorphisms does exist in the literature, and further studies will be necessary to consolidate our understanding of these multi-faceted proteins.

1. Introduction

Cerebrovascular disease (CVD) is characterized by brain ischemia that results in focal, acute neurological deficits and remains the fifth leading cause of death in the United States [1]. Over eighty percent of CVD consist of ischemic stroke (IS), defined by focal blood vessel occlusion. The main mechanisms of IS are thrombosis, embolization, and lacunar infarction that result in oxygen loss and ATPase dysfunction. The resulting cerebral ischemia initiates several pathological events including blood-brain barrier (BBB) disruption, vasogenic edema, secondary hemorrhagic transformation, and neuronal death.
The principal risk factors for IS incidence remains the metabolic syndrome, characterized by the co-incidence of hypertension, diabetes, obesity, high triglycerides, and low high-density lipoprotein [2,3]. More recently, IS incidence has also been found to be associated with environmental exposures such as alcohol, smoking, diet, and exercise [4,5].
However, not all individuals exposed to similar environmental factors suffer equally from IS. Differences in incidence, pathogenesis, and clinical outcome have long been noted when comparing IS among patients with different racial and ethnic backgrounds. Epidemiological studies highlight significant racial disparities with blacks having significantly higher stroke incidence compared to whites [6], younger age of incidence [7], and poorer functional outcomes [8].
Still, clinical, environmental, and demographic risk factors do not fully explain disparities in IS disease progression [9]. As with many other diseases, IS results from the interaction between an individual’s genetic makeup and environmental exposures [10]. For instance, high-density lipoprotein cholesterol and smoking in blacks, systolic blood pressure in Asians, and age in both Hispanics and blacks resulted in different atherosclerotic disease progression compared to whites [11]. Asians and Hispanics were found to have slower progression of carotid intima-media thickness, and blacks had less carotid plaque formation [12]. Finally, one study showed that blood pressure significantly correlated with stroke incidence in South Asian males, but not in European males [13]. Improved understanding has suggested a role for genetics in IS susceptibility [14].
Significant research has been carried out to establish the relationship between functional variants of different genes and IS risk [15,16,17,18,19,20,21]. One such potential genetic risk factor may be matrix metalloproteinase (MMP) polymorphisms [22]. The role of MMP polymorphisms in gene transcription and their associations with various diseases has been evaluated. Roles for specific MMP polymorphisms have been found in cancer incidence [23], coronary artery disease [24], and glaucoma [25]. Not surprisingly, burgeoning research in MMP polymorphisms for various types of populations have been conducted in IS as well. This review will evaluate MMP polymorphisms and provide some insight into their roles in IS incidence and clinical outcome.

2. Background on Matrix Metalloproteinases

MMPs are members of a unique family of zinc-binding endopeptidases that are secreted as catalytically latent species and processed to their activated forms in vivo by other proteases, the tissue plasminogen activator-plasmin system, or post-translational modifications [26,27,28]. At least twenty-five different MMPs have been identified [29]. Members of this protease family have been divided into five subclasses based on structural similarity and substrate specificity that include the following: collagenases (MMP-1, MMP-8, and MMP-13) [30,31,32], gelatinases (MMP-2 and MMP-9) [33,34,35], stromelysins (MMP-3 and MMP-10) [36,37], metalloelastases [38,39], membrane-type MMPs (MT-MMP, MMP-14, MMP 15, MMP-16, MMP-17, MMP-24, and MMP-25) [40,41,42,43,44,45], and others (MMP-7, MMP-11, MMP-12, MMP-19, MMP-20 and MMP-23) [46,47].
As ubiquitous proteins, MMPs have extensive roles that include epithelial repair against pathogens in innate immunity [48,49], control of chemokine activity (including CCL-2, 7, 8, and 13) [50], and the activation of inflammatory cytokines (interferon-β, vascular endothelial growth factor, epidermal growth factors, fibroblast growth factors, and transforming growth factor-β1) [51]. However, MMPs also play a significant role in normal and pathological conditions that involve ECM degradation and remodeling [52].
MMPs have also been shown to be involved in the complex pathophysiology of IS. Mechanisms of MMP in IS include atherosclerotic plaque maturation, plaque degradation and rupture [53], development of subclinical periventricular white matter disease (i.e., leukoaraiosis) [54], and hemorrhagic transformation (HT) particularly after thrombolysis [55]. While MMP-8 [56] and MMP-10 [57] have been related to atherosclerosis and brain ischemic, respectively, MMP-1, 2, 3, 9, and 12 have been most identified in the pathophysiology of IS. We will discuss each of these in turn.

3. Matrix Metalloproteinase-1

MMP-1 is a 53 kDa protein that plays an active role in the degradation of interstitial collagen types I, II, and III, and major structural components of the fibrous plaque, which forms the mechanism behind atherosclerotic stroke. The active-site zinc works with a hinge region and carboxyl terminal domain to unwind the triple-helical collagen structure [58]. Although implicated in neuronal cell death [59], MMP-1 has also been closely linked to advanced atherosclerotic plaques and has been postulated to exacerbate atherosclerosis by degrading plaques, which leads to a cycle of plaque expansion and rupture [53].

Clinical Role of MMP-1 Polymorphisms

A single-guanine (1G to 2G) polymorphism located at the MMP-1 promoter region -1607 1G/2G has been identified. The 2G-allele of this promoter has been noted to increase transcriptional activity by creating an E26 transcription factor binding site [60]. But Chehaibi et al. evaluated the role of this 1G vs. 2G allele in IS incidence in Tunisian patients and did not find any association between the -1607 promoter gene polymorphism and IS incidence [61]. But this failed association might be due to the similarities in genotype frequency between patients with carotid artery atherosclerosis and controls (p = 0.085). However, MMP-1 2G/2G homozygotes and MMP-3 polymorphisms were shown to synergistically lead to an increase in carotid atherosclerosis (odds ratio (OR) 3.31, p = 0.004) [62].
To date, no clinical study has evaluated the role of MMP-1 polymorphisms in clinical outcome of IS, and their role in IS incidence remains undetermined.

4. Matrix Metalloproteinase-2

MMP-2 (gelatinase-A) is a 72 kDa protein that degrades collagen IV, fibronectin, laminin, aggrecan, gelatin, elastin and non-matrix substrates, latent TGFβ9, monocyte chemoattractant protein-3, fibroblast growth factor receptor 1, big endothelin-1, and plasminogen. MMP-2 has several roles in IS. It disrupts the BBB and leads to HT [63]. It is also extensively associated with leukoaraiosis. This has been shown in animal models utilizing MMP-2 knockout mice and the corresponding inhibitors that significantly decreased chronic white matter disease [64]. Pathological studies demonstrated that MMP-2 levels are higher in patients with vascular dementia [65] and lacunar strokes [66]. Yet, MMP-2 serum levels immediately after acute IS are not markedly elevated [66,67]. However, the activity of MMP-2 increases in the late phase of IS [66,67,68], suggesting that it plays a neuroprotective role within the ischemic core.

Clinical Role of MMP-2 Polymorphisms

Five MMP-2 polymorphisms have been found to be associated with the development of lacunar strokes [69]. However, only a few MMP-2 genetic studies demonstrate its role in atherosclerotic disease. Price et al. identified a -1306 (C vs. T allele) polymorphism in the promoter region of MMP-2. This C to T transition disrupted the promoter, leading to lower MMP-2 expression and enzymatic activity [70].
One mechanism potentially linking MMP-2 with increased IS incidence is its association with leukoaraiosis. Zhang et al. evaluated the -1306 C/T promoter of MMP-2 in a Chinese population and found the CC genotype resulted in higher transcriptional activity and independently predicted leukoaraiosis (p = 0.027) [71]. However, Nie et al. evaluated this same promoter in a Chinese population and did not find an association between the CC genotype and IS incidence [72]. Instead, they found the -735 C-allele (C vs. T allele) in the MMP-2 promoter region was associated with a greater incidence of IS (OR 1.516, 95% confidence interval (CI) 1.185–1.940, p = 0.001) in their Chinese population. The C-allele of the -735 promoter is associated with significantly higher MMP-2 transcriptional activity [72]. High MMP-2 production and activity may be one risk factor for IS incidence.
Unlike other MMPs, the presence of elevated MMP-2 after IS in the acute phase has been associated with improved clinical outcome [66]. Manso et al. found significant associations between two single-nucleotide polymorphisms (SNP) rs2241145 and rs1992116 and clinical outcome after Bonferroni correction. For rs2241145 (G vs. C allele), the G-allele was significantly associated with good outcome after stroke (OR 1.66, 95% CI 1.20–2.30, p = 0.0439). In rs1992116 (G vs. A allele), the G-allele was significantly associated with improved outcome after stroke (OR 1.67, 95% CI 1.20–2.31, p = 0.0385) [73]. However, the relationship between these polymorphisms and transcriptional activity is unclear and is an area in need of further research.

5. Matrix Metalloproteinase-3

MMP-3 (stromelysin-1), is a 51 kDa protein produced by various cells types, including fibroblasts, smooth muscle cells, and macrophages. MMP-3 degrades major ECM components—collagens I, III, IV, V, IX, and X [74], fibronectin, denatured collagens, laminin, and cartilage proteoglycans [75]. Studies have consistently noted a role for MMP-3 in progression of carotid atherosclerosis [76]. MMP-3 is upregulated in infarcted human brain after IS [57], and high MMP-3 expression has been found to be associated with increased ischemic brain injury [77].

Clinical Role of MMP-3 Polymorphisms

MMP-3 polymorphisms in both promoter and coding regions have been linked to IS incidence. However, the role of MMP-3 polymorphisms in clinical outcomes has remained controversial with conflicting associations between polymorphisms and IS incidence and clinical outcome when studied in different racial and ethnic populations [78].
A variant in the promoter region of the MMP-3 gene -1612 (5A vs. 6A) was found to regulate the transcription of MMP-3 [79,80]. This variant has been studied extensively with the 6A-allele found to be associated with carotid artery atherosclerosis (OR 1.58, 95% CI 1.08–2.33, p = 0.017) [62]. In a Finnish population, homozygotes for the 6A-allele appeared to be predisposed to arterial wall thickening [79]. Patients with the 6A/6A genotype in MMP-3 also had significantly greater intima-media thickness when compared to 5A/5A and 5A/6A genotypes (p < 0.03) [81]. Finally, Rundek et al. found patients with the 6A/6A genotype in MMP-3 to have significantly greater intima-media thickness in comparison to 5A/5A and 5A/6A genotypes (p = 0.044) [82] and therefore a potential predictor for atherosclerotic IS. The 6A-allele is associated with decreased MMP-3 expression [83].
Flex et al. found the 5A-allele of the -1171 (5A vs. 6A allele) promoter region polymorphism in MMP-3 was significantly associated with IS incidence in an Italian population (OR 2.2, 95% CI 1.1–4.2, p = 0.01) [84]. The 5A-allele has higher promoter activity and higher MMP-3 transcriptional activity [85]. However, this may not be true in a heterozygous state as no association between the -1171 5A/6A polymorphism and IS incidence was found in an Indian population [86]. Adding to the controversy, Sherva et al. studied MMP-3 polymorphisms in 39,114 patients from the United States, Canada, Puerto Rico, and US Virgin Islands in the Genetics of Hypertension Associated Treatment study and conversely found the 6A/6A genotype to be associated with higher IS incidence in patients randomized to take lisinopril for hypertension [87].
Association of IS incidence with polymorphisms in the coding regions of MMP-3 have been shown to be dependent on ethnicity. Three SNPs [rs520540 (Ala362Ala), rs602128 (Asp96Asp), and rs679620 (Lys45Glu)] in the coding region of MMP-3 were significantly associated with IS (p < 0.05) in a Korean population. However, haplotype analysis revealed that no combination of these SNPs was associated with IS [78]. Conversely, Matarin et al. found no association between IS incidence and rs520540 and/or rs679620 gene polymorphisms in a North American population of European descent [88]. To date, no MMP-3 polymorphisms have been associated with IS clinical outcome.

6. Matrix Metalloproteinase-9

MMP-9 (gelatinase B), is a 92 kDa protein that cleaves most ECM proteins, particularly collagen types IV [35,89] and V [90]. It also activates numerous pro-inflammatory cytokines and chemokines such as CXCL-8, interleukin 1β, and tumor necrosis factor-α. MMP-9 is involved in inflammatory responses trigged by ischemia. In addition, due to digestion of type IV collagen, it facilitates leukocytes transport across the endothelium. Moreover, by digesting occludins and claudins, MMP-9 plays an important role in BBB destruction. Finally, elevated intranuclear MMP-9 degrades poly-ADP-ribose polymerase-1 and X-ray cross-complementary factor 1 [91] and promotes accumulation of damaged DNA in neurons [92].
Thus, MMP-9 is involved in BBB destruction [93] and subsequent HT [94] that occurs particularly after thrombolysis [55,95]. MMP-9 is also involved in generation of free radicals that result in atherosclerotic lesions [96], plaque rupture in carotid atherosclerotic plaques [97], coronary artery plaque destabilization and rupture with subsequent myocardial infarctions [98,99], and embolic IS [100]. The high concentration of MMP-9 in plasma within the acute phase of IS increases the risk of HT within the ischemic core [101,102]. MMP-9 mRNA concentration was a predictor of poor outcome and mortality in IS [103].

Clinical Role of MMP-9 Polymorphisms

Polymorphisms in the promoter and coding regions of MMP-9 have been associated with carotid atherosclerosis. Lin et al. found that post-menopausal women carrying T-alleles (C/T and T/T) at position -1562 in the promoter region of MMP-9 had stiffer arteries than patients with C/C genotypes even after adjusting for age and metabolic covariates [104]. Armstrong et al. evaluated the R279Q polymorphism (R vs. Q allele) and found that the R/R genotype resulted in significantly more carotid intima-media thickness when compared to the R/Q or Q/Q genotype (p = 0.006) [105].
Unsurprisingly, with evidence linking MMP-9 and its polymorphisms to carotid artery atherosclerosis, studies show that MMP-9 polymorphisms are also associated with increased IS incidence. Yuan et al. studied rs1056628 (A vs. C allele) in a Chinese population and noted dose-dependent increased expression of the C-allele (p < 0.01) and CC genotype (p < 0.05) in IS patients when compared to controls [106]. The promoter region -1562 (C vs. T allele) polymorphism was also shown to influence IS incidence with the T-allele associated with increased IS incidence (OR 1.543, 95% CI 1.144–2.080, p = 0.004) [72].
Although extensive evidence shows an association between MMP-9 expression and HT [94,102] particularly after administration of intravenous thrombolysis [55,95,107], the effect of MMP-9 polymorphisms on HT susceptibility is unclear. Zhang et al. evaluated the -1562 (C vs. T allele) promoter region polymorphism in a Chinese population and found that the C/C genotype was associated with significantly more HT compared to the C/T and T/T genotype (p = 0.037), and the frequency of the C-allele was significantly higher in patients with HT compared to the T-allele (p = 0.035) [108]. However, the -1562 C/T polymorphism did not play a role in HT after systemic thrombolysis in a Mediterranean population [109].
Despite extensive evidence linking MMP-9 expression with worse clinical outcome in IS, the role of MMP-9 polymorphisms remains unclear [110] and to date, no MMP-9 polymorphisms have been associated with clinical outcome in IS [73].

7. Matrix Metalloproteinase-12

Macrophage metalloelastase (MMP-12) is secreted as a 54 kDa pro-form protein that undergoes self-activation through autolytic processing to produce 45 kDa and 22 kDa active forms. MMP-12 plays a significant role in the pathophysiology of IS. It displays a broad substrate specificity, including degradation of the extracellular proteins—fibronectin, laminin, elastin, vitronectin, type IV collagen, and heparan sulfate [111,112,113]. Thus, MMP-12 enables macrophages to penetrate injured tissues during inflammation and facilitates monocytes transmigration across the endothelium [111,112]. In addition to digesting basement membrane components, MMP-12 also activates MMP-2 and MMP-3 [114], thus, synergistically activating a cascade of proteolytic processes, which ultimately lead to BBB disruption.

Clinical Role of MMP-12 Polymorphisms

Similar to other MMPs, MMP-12 polymorphisms have been found to play a role in the development of carotid atherosclerosis, which may be a potential mechanism in the association between certain alleles and IS incidence. The MMP-12 polymorphism rs660599 was found to be significantly overexpressed in patients with carotid plaques compared to atherosclerosis-free controls (p = 1.2 × 10−15) [115].
Chehaibi et al. suggested that the MMP-12 promoter polymorphism rs2276109 (A vs. G allele) may be a risk factor for IS in diabetic patients. They reported that the MMP-12 rs2276109 AA genotype was significantly associated with IS incidence in a Tunisian population (OR 1.79, 95% CI 1.29–2.69, p = 0.001). This relationship, however, was not found to be replicated in a non-diabetic population. The A-allele of the MMP-12 rs2276109 polymorphism (A vs. G allele) has been shown to have a higher affinity for the transcription factor activator protein-1 [116], resulting in increased expression of MMP-12 [61].
Similarly, the MMP-12 rs652438 (357 Asn/Ser) polymorphism, located in the coding region of the hemopexin domain that is responsible for MMP-12 activity [117], was found to be associated with IS incidence in diabetic individuals (adjusted OR 1.68, 95% CI 1.22–2.56, p = 0.001) [61]. However, to date, no direct association between MMP-12 polymorphisms and clinical outcome in IS has been reported.

8. Conclusions

The clinical roles for MMP polymorphisms are complex due to multifactorial mechanisms. Progression of carotid artery atherosclerosis (Table 1) represents a major pathophysiological mechanism responsible for IS incidence. However, as shown when comparing MMP polymorphisms responsible for IS incidence (Table 2) with polymorphisms responsible for carotid artery atherosclerosis, these polymorphisms do not necessarily lead to straightforward associations. Similarly, the multifactorial mechanisms and past medical history associated with clinical outcome after IS makes targeting the association between specific polymorphisms and clinical outcome extremely difficult (Table 3). Although several MMPs have a well-established relationship with HT, there is a less clear relationship between certain MMP polymorphisms and HT (Table 4).

9. Future Studies of Investigation

The classification of MMPs into their respective roles represents a challenging question for future study. First, individual MMPs must be studied further to evaluate for their respective roles in CVD pathology. The most important and widely-studied MMPs appear to be MMP-2, 3, 9, and 12. Second, once the important MMPs are targeted, the functional genetic variations of each of these MMPs must be addressed. Third, the role of these MMP polymorphisms in protein activity and transcriptional activity must be better characterized. Fourth, the association between these polymorphisms and ethnic disparities in clinical outcome after stroke must be related [8]. And finally, as ubiquitous proteins that appear to have both pathological and neuroprotective roles [118], the mechanism of action of these MMPs must be better characterized.

Author Contributions

Jason J. Chang study concept and design, writing of manuscript and revision, critical revision of manuscript for important intellectual content. Ansley Stanfill critical revision of manuscript for important intellectual content. Tayebeh Pourmotabbed study concept and design, critical revision of manuscript for important intellectual content.

Conflicts of Interest

Jason J. Chang reports no disclosures. Ansley Stanfill reports no disclosures. Tayebeh Pourmotabbed reports no disclosures.

References

  1. Murphy, S.L.; Xu, J.; Kochanek, K.D.; Bastian, B.A. Deaths: Final data for 2013. Natl. Vital Stat. Rep. 2016, 64, 1–119. [Google Scholar] [CrossRef]
  2. Wang, J.; Ruotsalainen, S.; Moilanen, L.; Lepisto, P.; Laakso, M.; Kuusisto, J. The metabolic syndrome predicts incident stroke: A 14-year follow-up study in elderly people in finland. Stroke 2008, 39, 1078–1083. [Google Scholar] [CrossRef] [PubMed]
  3. Koren-Morag, N.; Goldbourt, U.; Tanne, D. Relation between the metabolic syndrome and ischemic stroke or transient ischemic attack: A prospective cohort study in patients with atherosclerotic cardiovascular disease. Stroke 2005, 36, 1366–1371. [Google Scholar] [CrossRef] [PubMed]
  4. Kwon, Y.; Norby, F.L.; Jensen, P.N.; Agarwal, S.K.; Soliman, E.Z.; Lip, G.Y.; Longstreth, W.T., Jr.; Alonso, A.; Heckbert, S.R.; Chen, L.Y. Association of smoking, alcohol, and obesity with cardiovascular death and ischemic stroke in atrial fibrillation: The atherosclerosis risk in communities (ARIC) study and cardiovascular health study (CHS). PLoS ONE 2016, 11, e0147065. [Google Scholar] [CrossRef] [PubMed]
  5. O’Donnell, M.J.; Chin, S.L.; Rangarajan, S.; Xavier, D.; Liu, L.; Zhang, H.; Rao-Melacini, P.; Zhang, X.; Pais, P.; Agapay, S.; et al. Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (interstroke): A case-control study. Lancet 2016. [Google Scholar] [CrossRef]
  6. Kleindorfer, D.O.; Khoury, J.; Moomaw, C.J.; Alwell, K.; Woo, D.; Flaherty, M.L.; Khatri, P.; Adeoye, O.; Ferioli, S.; Broderick, J.P.; et al. Stroke incidence is decreasing in whites but not in blacks: A population-based estimate of temporal trends in stroke incidence from the greater cincinnati/northern kentucky stroke study. Stroke 2010, 41, 1326–1331. [Google Scholar] [CrossRef] [PubMed]
  7. Boan, A.D.; Feng, W.W.; Ovbiagele, B.; Bachman, D.L.; Ellis, C.; Adams, R.J.; Kautz, S.A.; Lackland, D.T. Persistent racial disparity in stroke hospitalization and economic impact in young adults in the buckle of stroke belt. Stroke 2014, 45, 1932–1938. [Google Scholar] [CrossRef] [PubMed]
  8. Ellis, C.; Boan, A.D.; Turan, T.N.; Ozark, S.; Bachman, D.; Lackland, D.T. Racial differences in poststroke rehabilitation utilization and functional outcomes. Arch. Phys. Med. Rehabil. 2015, 96, 84–90. [Google Scholar] [CrossRef] [PubMed]
  9. Howard, G.; Cushman, M.; Kissela, B.M.; Kleindorfer, D.O.; McClure, L.A.; Safford, M.M.; Rhodes, J.D.; Soliman, E.Z.; Moy, C.S.; Judd, S.E.; et al. Traditional risk factors as the underlying cause of racial disparities in stroke: Lessons from the half-full (empty?) glass. Stroke 2011, 42, 3369–3375. [Google Scholar] [CrossRef] [PubMed]
  10. Flossmann, E.; Schulz, U.G.; Rothwell, P.M. Systematic review of methods and results of studies of the genetic epidemiology of ischemic stroke. Stroke 2004, 35, 212–227. [Google Scholar] [CrossRef] [PubMed]
  11. Gijsberts, C.M.; Groenewegen, K.A.; Hoefer, I.E.; Eijkemans, M.J.; Asselbergs, F.W.; Anderson, T.J.; Britton, A.R.; Dekker, J.M.; Engstrom, G.; Evans, G.W.; et al. Race/ethnic differences in the associations of the framingham risk factors with carotid imt and cardiovascular events. PLoS ONE 2015, 10, e0132321. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Tattersall, M.C.; Gassett, A.; Korcarz, C.E.; Gepner, A.D.; Kaufman, J.D.; Liu, K.J.; Astor, B.C.; Sheppard, L.; Kronmal, R.A.; Stein, J.H. Predictors of carotid thickness and plaque progression during a decade: The multi-ethnic study of atherosclerosis. Stroke 2014, 45, 3257–3262. [Google Scholar] [CrossRef] [PubMed]
  13. Eastwood, S.V.; Tillin, T.; Chaturvedi, N.; Hughes, A.D. Ethnic differences in associations between blood pressure and stroke in south asian and european men. Hypertension 2015, 66, 481–488. [Google Scholar] [CrossRef] [PubMed]
  14. Meschia, J.F.; Brott, T.G.; Brown, R.D., Jr. Genetics of cerebrovascular disorders. Mayo Clin. Proc. 2005, 80, 122–132. [Google Scholar] [CrossRef]
  15. Dichgans, M. Genetics of ischaemic stroke. Lancet Neurol. 2007, 6, 149–161. [Google Scholar] [CrossRef]
  16. Munshi, A.; Kaul, S. Stroke genetics—Focus on PDE4D gene. Int. J. Stroke 2008, 3, 188–192. [Google Scholar] [CrossRef] [PubMed]
  17. Munshi, A.; Aliya, N.; Jyothy, A.; Kaul, S.; Alladi, S.; Shafi, G. Prothombin gene G20210A mutation is not a risk factor for ischemic stroke in a south indian hyderabadi population. Thromb. Res. 2009, 124, 245–247. [Google Scholar] [CrossRef] [PubMed]
  18. Munshi, A.; Sultana, S.; Kaul, S.; Reddy, B.P.; Alladi, S.; Jyothy, A. Angiotensin-converting enzyme insertion/deletion polymorphism and the risk of ischemic stroke in a South Indian population. J. Neurol. Sci. 2008, 272, 132–135. [Google Scholar] [CrossRef] [PubMed]
  19. Munshi, A.; Babu, M.S.; Kaul, S.; Shafi, G.; Anila, A.N.; Alladi, S.; Jyothy, A. Phosphodiesterase 4D (PDE4D) gene variants and the risk of ischemic stroke in a South Indian population. J. Neurol. Sci. 2009, 285, 142–145. [Google Scholar] [CrossRef] [PubMed]
  20. Munshi, A.; Rajeshwar, K.; Kaul, S.; Chandana, E.; Shafi, G.; Anila, A.N.; Balakrishna, N.; Alladi, S.; Jyothy, A. Vntr polymorphism in intron 4 of the enos gene and the risk of ischemic stroke in a South Indian population. Brain Res. Bull. 2010, 82, 247–250. [Google Scholar] [CrossRef] [PubMed]
  21. Munshi, A.; Sharma, V.; Kaul, S.; Rajeshwar, K.; Babu, M.S.; Shafi, G.; Anila, A.N.; Balakrishna, N.; Alladi, S.; Jyothy, A. Association of the -344C/T aldosterone synthase (CYP11B2) gene variant with hypertension and stroke. J. Neurol. Sci. 2010, 296, 34–38. [Google Scholar] [CrossRef] [PubMed]
  22. Abilleira, S.; Bevan, S.; Markus, H.S. The role of genetic variants of matrix metalloproteinases in coronary and carotid atherosclerosis. J. Med. Genet. 2006, 43, 897–901. [Google Scholar] [CrossRef] [PubMed]
  23. Liu, L.; Sun, J.; Li, G.; Gu, B.; Wang, X.; Chi, H.; Guo, F. Association between MMP-12-82A/G polymorphism and cancer risk: A meta-analysis. Int. J. Clin. Exp. Med. 2015, 8, 11896–11904. [Google Scholar] [PubMed]
  24. Jia, P.; Wu, N.; Zhang, X.; Jia, D. Association of matrix metalloproteinase-1-519A/G polymorphism with acute coronary syndrome: A meta-analysis. Int. J. Clin. Exp. Med. 2015, 8, 5675–5682. [Google Scholar] [PubMed]
  25. Zhang, Y.; Wang, M.; Zhang, S. Association of MMP-9 gene polymorphisms with glaucoma: A meta-analysis. Ophthalmic Res. 2016, 55, 172–179. [Google Scholar] [CrossRef] [PubMed]
  26. Woessner, J.F., Jr. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J. 1991, 5, 2145–2154. [Google Scholar] [PubMed]
  27. Matrisian, L.M. The matrix-degrading metalloproteinases. Bioessays 1992, 14, 455–463. [Google Scholar] [CrossRef] [PubMed]
  28. Birkedal-Hansen, H.; Moore, W.G.; Bodden, M.K.; Windsor, L.J.; Birkedal-Hansen, B.; DeCarlo, A.; Engler, J.A. Matrix metalloproteinases: A review. Crit. Rev. Oral Biol. Med. 1993, 4, 197–250. [Google Scholar] [PubMed]
  29. Kapoor, C.; Vaidya, S.; Wadhwan, V.; Hitesh, Kaur G.; Pathak, A. Seesaw of matrix metalloproteinases (MMPS). J. Cancer Res. Ther. 2016, 12, 28–35. [Google Scholar] [CrossRef] [PubMed]
  30. Goldberg, G.I.; Wilhelm, S.M.; Kronberger, A.; Bauer, E.A.; Grant, G.A.; Eisen, A.Z. Human fibroblast collagenase. Complete primary structure and homology to an oncogene transformation-induced rat protein. J. Biol. Chem. 1986, 261, 6600–6605. [Google Scholar] [PubMed]
  31. Hasty, K.A.; Pourmotabbed, T.F.; Goldberg, G.I.; Thompson, J.P.; Spinella, D.G.; Stevens, R.M.; Mainardi, C.L. Human neutrophil collagenase. A distinct gene product with homology to other matrix metalloproteinases. J. Biol. Chem. 1990, 265, 11421–11424. [Google Scholar] [PubMed]
  32. Freije, J.M.; Diez-Itza, I.; Balbin, M.; Sanchez, L.M.; Blasco, R.; Tolivia, J.; Lopez-Otin, C. Molecular cloning and expression of collagenase-3, a novel human matrix metalloproteinase produced by breast carcinomas. J. Biol. Chem. 1994, 269, 16766–16773. [Google Scholar] [PubMed]
  33. Collier, I.E.; Wilhelm, S.M.; Eisen, A.Z.; Marmer, B.L.; Grant, G.A.; Seltzer, J.L.; Kronberger, A.; He, C.S.; Bauer, E.A.; Goldberg, G.I. H-ras oncogene-transformed human bronchial epithelial cells (TBE-1) secrete a single metalloprotease capable of degrading basement membrane collagen. J. Biol. Chem. 1988, 263, 6579–6587. [Google Scholar] [PubMed]
  34. Wilhelm, S.M.; Collier, I.E.; Marmer, B.L.; Eisen, A.Z.; Grant, G.A.; Goldberg, G.I. SV40-transformed human lung fibroblasts secrete a 92-KDa type IV collagenase which is identical to that secreted by normal human macrophages. J. Biol. Chem. 1989, 264, 17213–17221. [Google Scholar] [PubMed]
  35. Pourmotabbed, T.; Solomon, T.L.; Hasty, K.A.; Mainardi, C.L. Characteristics of 92-KDa type IV collagenase/gelatinase produced by granulocytic leukemia cells: Structure, expression of cdna in E. coli and enzymic properties. Biochim. Biophys. Acta 1994, 1204, 97–107. [Google Scholar] [CrossRef]
  36. Whitham, S.E.; Murphy, G.; Angel, P.; Rahmsdorf, H.J.; Smith, B.J.; Lyons, A.; Harris, T.J.; Reynolds, J.J.; Herrlich, P.; Docherty, A.J. Comparison of human stromelysin and collagenase by cloning and sequence analysis. Biochem. J. 1986, 240, 913–916. [Google Scholar] [CrossRef] [PubMed]
  37. Muller, D.; Quantin, B.; Gesnel, M.C.; Millon-Collard, R.; Abecassis, J.; Breathnach, R. The collagenase gene family in humans consists of at least four members. Biochem. J. 1988, 253, 187–192. [Google Scholar] [CrossRef] [PubMed]
  38. Shapiro, S.D.; Griffin, G.L.; Gilbert, D.J.; Jenkins, N.A.; Copeland, N.G.; Welgus, H.G.; Senior, R.M.; Ley, T.J. Molecular cloning, chromosomal localization, and bacterial expression of a murine macrophage metalloelastase. J. Biol. Chem. 1992, 267, 4664–4671. [Google Scholar] [PubMed]
  39. Shapiro, S.D.; Kobayashi, D.K.; Ley, T.J. Cloning and characterization of a unique elastolytic metalloproteinase produced by human alveolar macrophages. J. Biol. Chem. 1993, 268, 23824–23829. [Google Scholar] [PubMed]
  40. Sato, H.; Takino, T.; Okada, Y.; Cao, J.; Shinagawa, A.; Yamamoto, E.; Seiki, M. A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature 1994, 370, 61–65. [Google Scholar] [CrossRef] [PubMed]
  41. Takino, T.; Sato, H.; Shinagawa, A.; Seiki, M. Identification of the second membrane-type matrix metalloproteinase (MT-MMP-2) gene from a human placenta cDNA library. MT-MMPs form a unique membrane-type subclass in the MMP family. J. Biol. Chem. 1995, 270, 23013–23020. [Google Scholar] [CrossRef] [PubMed]
  42. Will, H.; Hinzmann, B. cDNA sequence and mRNA tissue distribution of a novel human matrix metalloproteinase with a potential transmembrane segment. Eur. J. Biochem. 1995, 231, 602–608. [Google Scholar] [CrossRef] [PubMed]
  43. Puente, X.S.; Pendas, A.M.; Llano, E.; Velasco, G.; Lopez-Otin, C. Molecular cloning of a novel membrane-type matrix metalloproteinase from a human breast carcinoma. Cancer Res. 1996, 56, 944–949. [Google Scholar] [PubMed]
  44. Pei, D. Identification and characterization of the fifth membrane-type matrix metalloproteinase MT5-MMP. J. Biol. Chem. 1999, 274, 8925–8932. [Google Scholar] [CrossRef] [PubMed]
  45. Pei, D. Leukolysin/MMP25/MT6-MMP: A novel matrix metalloproteinase specifically expressed in the leukocyte lineage. Cell Res. 1999, 9, 291–303. [Google Scholar] [CrossRef] [PubMed]
  46. Nagase, H.; Woessner, J.F., Jr. Matrix metalloproteinases. J. Biol. Chem. 1999, 274, 21491–21494. [Google Scholar] [CrossRef] [PubMed]
  47. Okada, Y. Matrix-degrading metalloproteinases and their roles in joint destruction. Mod. Rheumatol. 2000, 10, 121–128. [Google Scholar] [CrossRef] [PubMed]
  48. Parks, W.C. Matrix metalloproteinases in repair. Wound Repair Regen. 1999, 7, 423–432. [Google Scholar] [CrossRef] [PubMed]
  49. Dunsmore, S.E.; Saarialho-Kere, U.K.; Roby, J.D.; Wilson, C.L.; Matrisian, L.M.; Welgus, H.G.; Parks, W.C. Matrilysin expression and function in airway epithelium. J. Clin. Investig. 1998, 102, 1321–1331. [Google Scholar] [CrossRef] [PubMed]
  50. McQuibban, G.A.; Gong, J.H.; Wong, J.P.; Wallace, J.L.; Clark-Lewis, I.; Overall, C.M. Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo. Blood 2002, 100, 1160–1167. [Google Scholar] [PubMed]
  51. Parks, W.C.; Wilson, C.L.; Lopez-Boado, Y.S. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat. Rev. Immunol. 2004, 4, 617–629. [Google Scholar] [CrossRef] [PubMed]
  52. Martin, M.D.; Matrisian, L.M. The other side of mmps: Protective roles in tumor progression. Cancer Metastasis Rev. 2007, 26, 717–724. [Google Scholar] [CrossRef] [PubMed]
  53. Nikkari, S.T.; O’Brien, K.D.; Ferguson, M.; Hatsukami, T.; Welgus, H.G.; Alpers, C.E.; Clowes, A.W. Interstitial collagenase (MMP-1) expression in human carotid atherosclerosis. Circulation 1995, 92, 1393–1398. [Google Scholar] [CrossRef] [PubMed]
  54. Corbin, Z.A.; Rost, N.S.; Lorenzano, S.; Kernan, W.N.; Parides, M.K.; Blumberg, J.B.; Milbury, P.E.; Arai, K.; Hartdegen, S.N.; Lo, E.H.; et al. White matter hyperintensity volume correlates with matrix metalloproteinase-2 in acute ischemic stroke. J. Stroke Cerebrovasc. Dis. 2014, 23, 1300–1306. [Google Scholar] [CrossRef] [PubMed]
  55. Inzitari, D.; Giusti, B.; Nencini, P.; Gori, A.M.; Nesi, M.; Palumbo, V.; Piccardi, B.; Armillis, A.; Pracucci, G.; Bono, G.; et al. MMP9 variation after thrombolysis is associated with hemorrhagic transformation of lesion and death. Stroke 2013, 44, 2901–2903. [Google Scholar] [CrossRef] [PubMed]
  56. Lenglet, S.; Mach, F.; Montecucco, F. Role of matrix metalloproteinase-8 in atherosclerosis. Mediat. Inflamm. 2013, 2013, 659282. [Google Scholar] [CrossRef] [PubMed]
  57. Cuadrado, E.; Rosell, A.; Penalba, A.; Slevin, M.; Alvarez-Sabin, J.; Ortega-Aznar, A.; Montaner, J. Vascular MMP-9/TIMP-2 and neuronal mmp-10 up-regulation in human brain after stroke: A combined laser microdissection and protein array study. J. Proteome Res. 2009, 8, 3191–3197. [Google Scholar] [CrossRef] [PubMed]
  58. Manka, S.W.; Carafoli, F.; Visse, R.; Bihan, D.; Raynal, N.; Farndale, R.W.; Murphy, G.; Enghild, J.J.; Hohenester, E.; Nagase, H. Structural insights into triple-helical collagen cleavage by matrix metalloproteinase 1. Proc. Natl. Acad. Sci. USA 2012, 109, 12461–12466. [Google Scholar] [CrossRef] [PubMed]
  59. Conant, K.; St Hillaire, C.; Nagase, H.; Visse, R.; Gary, D.; Haughey, N.; Anderson, C.; Turchan, J.; Nath, A. Matrix metalloproteinase 1 interacts with neuronal integrins and stimulates dephosphorylation of Akt. J. Biol. Chem. 2004, 279, 8056–8062. [Google Scholar] [CrossRef] [PubMed]
  60. Rutter, J.L.; Mitchell, T.I.; Buttice, G.; Meyers, J.; Gusella, J.F.; Ozelius, L.J.; Brinckerhoff, C.E. A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter creates an Ets binding site and augments transcription. Cancer Res. 1998, 58, 5321–5325. [Google Scholar] [PubMed]
  61. Chehaibi, K.; Hrira, M.Y.; Nouira, S.; Maatouk, F.; Ben Hamda, K.; Slimane, M.N. Matrix metalloproteinase-1 and matrix metalloproteinase-12 gene polymorphisms and the risk of ischemic stroke in a Tunisian population. J. Neurol. Sci. 2014, 342, 107–113. [Google Scholar] [CrossRef] [PubMed]
  62. Ghilardi, G.; Biondi, M.L.; DeMonti, M.; Turri, O.; Guagnellini, E.; Scorza, R. Matrix metalloproteinase-1 and matrix metalloproteinase-3 gene promoter polymorphisms are associated with carotid artery stenosis. Stroke 2002, 33, 2408–2412. [Google Scholar] [CrossRef] [PubMed]
  63. Batra, A.; Latour, L.L.; Ruetzler, C.A.; Hallenbeck, J.M.; Spatz, M.; Warach, S.; Henning, E.C. Increased plasma and tissue MMP levels are associated with BCSFB and BBB disruption evident on post-contrast flair after experimental stroke. J. Cereb. Blood Flow Metab. 2010, 30, 1188–1199. [Google Scholar] [CrossRef] [PubMed]
  64. Nakaji, K.; Ihara, M.; Takahashi, C.; Itohara, S.; Noda, M.; Takahashi, R.; Tomimoto, H. Matrix metalloproteinase-2 plays a critical role in the pathogenesis of white matter lesions after chronic cerebral hypoperfusion in rodents. Stroke 2006, 37, 2816–2823. [Google Scholar] [CrossRef] [PubMed]
  65. Rosenberg, G.A.; Sullivan, N.; Esiri, M.M. White matter damage is associated with matrix metalloproteinases in vascular dementia. Stroke 2001, 32, 1162–1168. [Google Scholar] [CrossRef] [PubMed]
  66. Lucivero, V.; Prontera, M.; Mezzapesa, D.M.; Petruzzellis, M.; Sancilio, M.; Tinelli, A.; di Noia, D.; Ruggieri, M.; Federico, F. Different roles of matrix metalloproteinases-2 and -9 after human ischaemic stroke. Neurol. Sci. 2007, 28, 165–170. [Google Scholar] [CrossRef] [PubMed]
  67. Clark, A.W.; Krekoski, C.A.; Bou, S.S.; Chapman, K.R.; Edwards, D.R. Increased gelatinase a (MMP-2) and gelatinase B (MMP-9) activities in human brain after focal ischemia. Neurosci. Lett. 1997, 238, 53–56. [Google Scholar] [CrossRef]
  68. Rosenberg, G.A.; Cunningham, L.A.; Wallace, J.; Alexander, S.; Estrada, E.Y.; Grossetete, M.; Razhagi, A.; Miller, K.; Gearing, A. Immunohistochemistry of matrix metalloproteinases in reperfusion injury to rat brain: Activation of MMP-9 linked to stromelysin-1 and microglia in cell cultures. Brain Res. 2001, 893, 104–112. [Google Scholar] [CrossRef]
  69. Fatar, M.; Stroick, M.; Steffens, M.; Senn, E.; Reuter, B.; Bukow, S.; Griebe, M.; Alonso, A.; Lichtner, P.; Bugert, P.; et al. Single-nucleotide polymorphisms of MMP-2 gene in stroke subtypes. Cerebrovasc. Dis. 2008, 26, 113–119. [Google Scholar] [CrossRef] [PubMed]
  70. Price, S.J.; Greaves, D.R.; Watkins, H. Identification of novel, functional genetic variants in the human matrix metalloproteinase-2 gene: Role of Sp1 in allele-specific transcriptional regulation. J. Biol. Chem. 2001, 276, 7549–7558. [Google Scholar] [CrossRef] [PubMed]
  71. Zhang, M.; Zhu, W.; Yun, W.; Wang, Q.; Cheng, M.; Zhang, Z.; Liu, X.; Zhou, X.; Xu, G. Correlation of matrix metalloproteinase-2 single nucleotide polymorphisms with the risk of small vessel disease (SVD). J. Neurol. Sci. 2015, 356, 61–64. [Google Scholar] [CrossRef] [PubMed]
  72. Nie, S.W.; Wang, X.F.; Tang, Z.C. Correlations between MMP-2/MMP-9 promoter polymorphisms and ischemic stroke. Int. J. Clin. Exp. Med. 2014, 7, 400–404. [Google Scholar] [PubMed]
  73. Manso, H.; Krug, T.; Sobral, J.; Albergaria, I.; Gaspar, G.; Ferro, J.M.; Oliveira, S.A.; Vicente, A.M. Variants of the matrix metalloproteinase-2 but not the matrix metalloproteinase-9 genes significantly influence functional outcome after stroke. BMC Med. Genet. 2010. [Google Scholar] [CrossRef] [PubMed]
  74. Rosenberg, G.A. Matrix metalloproteinases in neuroinflammation. Glia 2002, 39, 279–291. [Google Scholar] [CrossRef] [PubMed]
  75. Klein, T.; Bischoff, R. Physiology and pathophysiology of matrix metalloproteases. Amino Acids 2011, 41, 271–290. [Google Scholar] [CrossRef] [PubMed]
  76. Henney, A.M.; Wakeley, P.R.; Davies, M.J.; Foster, K.; Hembry, R.; Murphy, G.; Humphries, S. Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization. Proc. Natl. Acad. Sci. USA 1991, 88, 8154–8158. [Google Scholar] [CrossRef] [PubMed]
  77. Liu, J.K.; Rosenberg, G.A. Matrix metalloproteinases and free radicals in cerebral ischemia. Free. Radic. Biol. Med. 2005, 39, 71–80. [Google Scholar]
  78. Kim, S.K.; Kang, S.W.; Kim, D.H.; Yun, D.H.; Chung, J.H.; Ban, J.Y. Matrix metalloproteinase-3 gene polymorphisms are associated with ischemic stroke. J. Interf. Cytokine 2012, 32, 81–86. [Google Scholar] [CrossRef] [PubMed]
  79. Rauramaa, R.; Vaisanen, S.B.; Luong, L.A.; Schmidt-Trucksass, A.; Penttila, I.M.; Bouchard, C.; Toyry, J.; Humphries, S.E. Stromelysin-1 and interleukin-6 gene promoter polymorphisms are determinants of asymptomatic carotid artery atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 2000, 20, 2657–2662. [Google Scholar] [CrossRef] [PubMed]
  80. Ye, S.; Watts, G.F.; Mandalia, S.; Humphries, S.E.; Henney, A.M. Preliminary report: Genetic variation in the human stromelysin promoter is associated with progression of coronary atherosclerosis. Br. Heart J. 1995, 73, 209–215. [Google Scholar] [CrossRef] [PubMed]
  81. Gnasso, A.; Motti, C.; Irace, C.; Carallo, C.; Liberatoscioli, L.; Bernardini, S.; Massoud, R.; Mattioli, P.L.; Federici, G.; Cortese, C. Genetic variation in human stromelysin gene promoter and common carotid geometry in healthy male subjects. Arterioscler. Thromb. Vasc. Biol. 2000, 20, 1600–1605. [Google Scholar] [CrossRef] [PubMed]
  82. Rundek, T.; Elkind, M.S.; Pittman, J.; Boden-Albala, B.; Martin, S.; Humphries, S.E.; Juo, S.H.; Sacco, R.L. Carotid intima-media thickness is associated with allelic variants of stromelysin-1, interleukin-6, and hepatic lipase genes: The Northern Manhattan prospective cohort study. Stroke 2002, 33, 1420–1423. [Google Scholar] [CrossRef] [PubMed]
  83. Kaplan, R.C.; Smith, N.L.; Zucker, S.; Heckbert, S.R.; Rice, K.; Psaty, B.M. Matrix metalloproteinase-3 (MMP3) and MMP9 genes and risk of myocardial infarction, ischemic stroke, and hemorrhagic stroke. Atherosclerosis 2008, 201, 130–137. [Google Scholar] [CrossRef] [PubMed]
  84. Flex, A.; Gaetani, E.; Papaleo, P.; Straface, G.; Proia, A.S.; Pecorini, G.; Tondi, P.; Pola, P.; Pola, R. Proinflammatory genetic profiles in subjects with history of ischemic stroke. Stroke 2004, 35, 2270–2275. [Google Scholar] [CrossRef] [PubMed]
  85. Ye, S.; Eriksson, P.; Hamsten, A.; Kurkinen, M.; Humphries, S.E.; Henney, A.M. Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression. J. Biol. Chem. 1996, 271, 13055–13060. [Google Scholar] [PubMed]
  86. Munshi, A.; Rajeshwar, K.; Kaul, S.; Al-Hazzani, A.; Alshatwi, A.A.; Shafi, G.; Balakrishna, N.; Jyothy, A. Association of tumor necrosis factor-α and matrix metalloproteinase-3 gene variants with stroke. Eur. J. Neurol. 2011, 18, 1053–1059. [Google Scholar] [CrossRef] [PubMed]
  87. Sherva, R.; Ford, C.E.; Eckfeldt, J.H.; Davis, B.R.; Boerwinkle, E.; Arnett, D.K. Pharmacogenetic effect of the stromelysin (MMP3) polymorphism on stroke risk in relation to antihypertensive treatment: The genetics of hypertension associated treatment study. Stroke 2011, 42, 330–335. [Google Scholar] [CrossRef] [PubMed]
  88. Matarin, M.; Brown, W.M.; Dena, H.; Britton, A.; De Vrieze, F.W.; Brott, T.G.; Brown, R.D., Jr.; Worrall, B.B.; Case, L.D.; Chanock, S.J.; et al. Candidate gene polymorphisms for ischemic stroke. Stroke 2009, 40, 3436–3442. [Google Scholar] [CrossRef] [PubMed]
  89. Fenhalls, G.; Geyp, M.; Dent, D.M.; Parker, M.I. Breast tumour cell-induced down-regulation of type I collagen mrna in fibroblasts. Br. J. Cancer 1999, 81, 1142–1149. [Google Scholar] [CrossRef] [PubMed]
  90. Buraczynska, K.; Kurzepa, J.; Ksiazek, A.; Buraczynska, M.; Rejdak, K. Matrix metalloproteinase-9 (MMP-9) gene polymorphism in stroke patients. Neuromol. Med. 2015, 17, 385–390. [Google Scholar] [CrossRef] [PubMed]
  91. Yang, Y.; Candelario-Jalil, E.; Thompson, J.F.; Cuadrado, E.; Estrada, E.Y.; Rosell, A.; Montaner, J.; Rosenberg, G.A. Increased intranuclear matrix metalloproteinase activity in neurons interferes with oxidative DNA repair in focal cerebral ischemia. J. Neurochem. 2010, 112, 134–149. [Google Scholar] [CrossRef] [PubMed]
  92. Hill, J.W.; Poddar, R.; Thompson, J.F.; Rosenberg, G.A.; Yang, Y. Intranuclear matrix metalloproteinases promote DNA damage and apoptosis induced by oxygen-glucose deprivation in neurons. Neuroscience 2012, 220, 277–290. [Google Scholar] [CrossRef] [PubMed]
  93. Barr, T.L.; Latour, L.L.; Lee, K.Y.; Schaewe, T.J.; Luby, M.; Chang, G.S.; El-Zammar, Z.; Alam, S.; Hallenbeck, J.M.; Kidwell, C.S.; et al. Blood-brain barrier disruption in humans is independently associated with increased matrix metalloproteinase-9. Stroke 2010, 41, e123–e128. [Google Scholar] [CrossRef] [PubMed]
  94. Jha, R.; Battey, T.W.; Pham, L.; Lorenzano, S.; Furie, K.L.; Sheth, K.N.; Kimberly, W.T. Fluid-attenuated inversion recovery hyperintensity correlates with matrix metalloproteinase-9 level and hemorrhagic transformation in acute ischemic stroke. Stroke 2014, 45, 1040–1045. [Google Scholar] [CrossRef] [PubMed]
  95. Montaner, J.; Molina, C.A.; Monasterio, J.; Abilleira, S.; Arenillas, J.F.; Ribo, M.; Quintana, M.; Alvarez-Sabin, J. Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation 2003, 107, 598–603. [Google Scholar] [CrossRef] [PubMed]
  96. Zalba, G.; Fortuno, A.; Orbe, J.; San Jose, G.; Moreno, M.U.; Belzunce, M.; Rodriguez, J.A.; Beloqui, O.; Paramo, J.A.; Diez, J. Phagocytic nadph oxidase-dependent superoxide production stimulates matrix metalloproteinase-9: Implications for human atherosclerosis. Arterioscle. Thromb. Vasc. Biol. 2007, 27, 587–593. [Google Scholar] [CrossRef] [PubMed]
  97. Heo, S.H.; Cho, C.H.; Kim, H.O.; Jo, Y.H.; Yoon, K.S.; Lee, J.H.; Park, J.C.; Park, K.C.; Ahn, T.B.; Chung, K.C.; et al. Plaque rupture is a determinant of vascular events in carotid artery atherosclerotic disease: Involvement of matrix metalloproteinases 2 and 9. J. Clin. Neurol. 2011, 7, 69–76. [Google Scholar] [CrossRef] [PubMed]
  98. Cimmino, G.; Ragni, M.; Cirillo, P.; Petrillo, G.; Loffredo, F.; Chiariello, M.; Gresele, P.; Falcinelli, E.; Golino, P. C-reactive protein induces expression of matrix metalloproteinase-9: A possible link between inflammation and plaque rupture. Int. J. Cardiol. 2013, 168, 981–986. [Google Scholar] [CrossRef] [PubMed]
  99. Koizumi, T.; Komiyama, N.; Nishimura, S. In-vivo higher plasma levels of platelet-derived growth factor and matrix metalloproteinase-9 in coronary artery at the very onset of myocardial infarction with ST-segment elevation. Ann. Vasc. Dis. 2015, 8, 297–301. [Google Scholar] [CrossRef] [PubMed]
  100. Rao, V.H.; Kansal, V.; Stoupa, S.; Agrawal, D.K. MMP-1 and MMP-9 regulate epidermal growth factor-dependent collagen loss in human carotid plaque smooth muscle cells. Physiol. Rep. 2014, 2, e00224. [Google Scholar] [CrossRef] [PubMed]
  101. Yamada, H.; Yoneda, M.; Inaguma, S.; Watanabe, D.; Banno, S.; Yoshikawa, K.; Mizutani, K.; Iwaki, M.; Zako, M. Infliximab counteracts tumor necrosis factor-alpha-enhanced induction of matrix metalloproteinases that degrade claudin and occludin in non-pigmented ciliary epithelium. Biochem. Pharmacol. 2013, 85, 1770–1782. [Google Scholar] [CrossRef] [PubMed]
  102. Montaner, J.; Alvarez-Sabin, J.; Molina, C.A.; Angles, A.; Abilleira, S.; Arenillas, J.; Monasterio, J. Matrix metalloproteinase expression is related to hemorrhagic transformation after cardioembolic stroke. Stroke 2001, 32, 2762–2767. [Google Scholar] [CrossRef] [PubMed]
  103. Graham, C.A.; Chan, R.W.; Chan, D.Y.; Chan, C.P.; Wong, L.K.; Rainer, T.H. Matrix metalloproteinase 9 mRNA: An early prognostic marker for patients with acute stroke. Clin. Biochem. 2012, 45, 352–355. [Google Scholar] [CrossRef] [PubMed]
  104. Lin, R.T.; Chen, C.H.; Tsai, P.C.; Ho, B.L.; Juo, S.H.; Lin, H.F. Sex-specific effect of matrix metalloproteinase-9 functional promoter polymorphism on carotid artery stiffness. Atherosclerosis 2012, 223, 416–420. [Google Scholar] [CrossRef] [PubMed]
  105. Armstrong, C.; Abilleira, S.; Sitzer, M.; Markus, H.S.; Bevan, S. Polymorphisms in MMP family and TIMP genes and carotid artery intima-media thickness. Stroke 2007, 38, 2895–2899. [Google Scholar] [CrossRef] [PubMed]
  106. Yuan, M.; Zhan, Q.; Duan, X.; Song, B.; Zeng, S.; Chen, X.; Yang, Q.; Xia, J. A functional polymorphism at miR-491-5p binding site in the 3’-UTR of MMP-9 gene confers increased risk for atherosclerotic cerebral infarction in a chinese population. Atherosclerosis 2013, 226, 447–452. [Google Scholar] [CrossRef] [PubMed]
  107. Ning, M.; Furie, K.L.; Koroshetz, W.J.; Lee, H.; Barron, M.; Lederer, M.; Wang, X.; Zhu, M.; Sorensen, A.G.; Lo, E.H.; et al. Association between tPA therapy and raised early matrix metalloproteinase-9 in acute stroke. Neurology 2006, 66, 1550–1555. [Google Scholar] [CrossRef] [PubMed]
  108. Zhang, X.; Cao, X.; Xu, X.; Li, A.; Xu, Y. Correlation between the -1562c/t polymorphism in the matrix metalloproteinase-9 gene and hemorrhagic transformation of ischemic stroke. Exp. Ther. Med. 2015, 9, 1043–1047. [Google Scholar] [CrossRef] [PubMed]
  109. Montaner, J.; Fernandez-Cadenas, I.; Molina, C.A.; Monasterio, J.; Arenillas, J.F.; Ribo, M.; Quintana, M.; Chacon, P.; Andreu, A.L.; Alvarez-Sabin, J. 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. Stroke 2003, 34, 2851–2855. [Google Scholar] [CrossRef] [PubMed]
  110. Ramos-Fernandez, M.; Bellolio, M.F.; Stead, L.G. Matrix metalloproteinase-9 as a marker for acute ischemic stroke: A systematic review. J. Stroke Cerebrovasc. Dis. 2011, 20, 47–54. [Google Scholar] [CrossRef] [PubMed]
  111. Chandler, S.; Cossins, J.; Lury, J.; Wells, G. Macrophage metalloelastase degrades matrix and myelin proteins and processes a tumour necrosis factor-alpha fusion protein. Biochem. Biophys. Res. Commun. 1996, 228, 421–429. [Google Scholar] [CrossRef] [PubMed]
  112. Gronski, T.J., Jr.; Martin, R.L.; Kobayashi, D.K.; Walsh, B.C.; Holman, M.C.; Huber, M.; van Wart, H.E.; Shapiro, S.D. Hydrolysis of a broad spectrum of extracellular matrix proteins by human macrophage elastase. J. Biol. Chem. 1997, 272, 12189–12194. [Google Scholar] [CrossRef] [PubMed]
  113. Fulcher, Y.G.; van Doren, S.R. Remote exosites of the catalytic domain of matrix metalloproteinase-12 enhance elastin degradation. Biochemistry 2011, 50, 9488–9499. [Google Scholar] [CrossRef] [PubMed]
  114. Matsumoto, S.; Kobayashi, T.; Katoh, M.; Saito, S.; Ikeda, Y.; Kobori, M.; Masuho, Y.; Watanabe, T. Expression and localization of matrix metalloproteinase-12 in the aorta of cholesterol-fed rabbits: Relationship to lesion development. Am. J. Pathol. 1998, 153, 109–119. [Google Scholar] [CrossRef]
  115. Traylor, M.; Makela, K.M.; Kilarski, L.L.; Holliday, E.G.; Devan, W.J.; Nalls, M.A.; Wiggins, K.L.; Zhao, W.; Cheng, Y.C.; Achterberg, S.; et al. A novel MMP12 locus is associated with large artery atherosclerotic stroke using a genome-wide age-at-onset informed approach. PLoS Genet. 2014, 10, e1004469. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Jormsjo, S.; Ye, S.; Moritz, J.; Walter, D.H.; Dimmeler, S.; Zeiher, A.M.; Henney, A.; Hamsten, A.; Eriksson, P. Allele-specific regulation of matrix metalloproteinase-12 gene activity is associated with coronary artery luminal dimensions in diabetic patients with manifest coronary artery disease. Circ. Res. 2000, 86, 998–1003. [Google Scholar] [CrossRef] [PubMed]
  117. Joos, L.; He, J.Q.; Shepherdson, M.B.; Connett, J.E.; Anthonisen, N.R.; Pare, P.D.; Sandford, A.J. The role of matrix metalloproteinase polymorphisms in the rate of decline in lung function. Hum. Mol. Genet. 2002, 11, 569–576. [Google Scholar] [CrossRef] [PubMed]
  118. 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, 2498–2505. [Google Scholar] [CrossRef] [PubMed]
Table
Table 1. Matrix metalloproteinase (MMP) polymorphism relation to carotid artery atherosclerosis and intima-media thickness.
Table 1. Matrix metalloproteinase (MMP) polymorphism relation to carotid artery atherosclerosis and intima-media thickness.
MMP StudiedPolymorphism StudiedGene RegionPopulation and/or LocationFindingsTranscriptional ActivityReference
MMP-1-1607 (1G/2G)PromoterTunisianNo differenceIncreased with 2G-allele[62]
MMP-35A/6APromoterTunisian6A-allele associated with ICA atherosclerosis *Decreased with 6A-allele[62]
MMP-35A/6APromoterUnknown6A-allele associated with ICA atherosclerosis ±Decreased with 6A-allele[81]
MMP-3-1612 (5A/ 6A)PromoterHispanic, Black, and White6A/6A genotype associated with greater carotid atherosclerosis ±Decreased with 6A-allele[82]
MMP-9-1562 (T/C)PromoterChinese, post-menopausal womenT-allele associated with stiffer arteries ±Increased with C-allele[104]
MMP-9R279Q (R/Q)CodingGermanR/R genotype associated with greater mean carotid intima-media thickness *n/a[105]
MMP-12-rs660599CodingUnknownSNP overexpressed in patients with carotid plaques *n/a[115]
* Association found via logistic regression analysis; ± Association found via multivariable linear regression analysis; n/a = not applicable.
Table
Table 2. MMP polymorphism relation to ischemic stroke incidence.
Table 2. MMP polymorphism relation to ischemic stroke incidence.
MMP StudiedPolymorphism StudiedGene RegionPopulation and/or LocationFindingTranscriptional ActivityReference
MMP-1-1607 (1G/2G)PromoterTunisianNo differenceIncreased with 2G-allele[61]
MMP-2-1306 (C/T)PromoterChineseC-allele associated with leukoaraiosis *Increased with C-allele[71]
MMP-2-1306 (C/T)PromoterChineseNo differenceIncreased with C-allele[72]
MMP-2-735 (C/T)PromoterChineseC-allele associated with greater incidence of IS *Increased with C-allele[72]
MMP-3-1171 (5A/6A)PromoterItalian5A-allele associated with greater incidence of IS *Increased with 5A-allele[84]
MMP-3-5A/6APromoterMulti-racial6A/6A genotype associated with greater incidence of IS in patients taking lisinoprilIncreased with 5A-allele[87]
MMP-3-rs520540 (G/A)CodingKoreanG-allele associated with greater incidence of ISn/a[78]
MMP-3-rs520540 (G/A)CodingUnknownNo differencen/a[88]
MMP-3-rs3025058 (5A/6A)CodingKoreanG/G and G/A genotype associated with greater incidence of ISn/a[78]
MMP-3-rs3025058 (5A/6A)CodingUnknownNo differencen/a[88]
MMP-3-rs679620 (G/A)CodingKoreanG-allele associated with greater incidence of IS in women onlyn/a[78]
MMP-3-rs679620 (G/A)CodingUnknownNo differencen/a[88]
MMP-3-rs602128 (C/T)CodingKoreanC-allele associated with greater incidence of ISn/a[78]
MMP-9-rs1056628 (A/C)CodingChineseC/C genotype associated with greater incidence of ISn/a[106]
MMP-9-1562 (C/T)PromoterChineseT/T genotype associated with greater incidence of IS *Increased with T-allele[72]
MMP-12-rs2276109 [82] (A/G)PromoterTunisianA/A genotype associated with greater incidence of IS *Increased with A-allele[61]
MMP-12-rs652438 [1082] (A/G)PromoterTunisianA/A genotype associated with greater incidence of IS *Increased with A-allele[61]
MMP-12-rs660599CodingUnknownReplication of SNP associated with greater incidence of IS with large-artery mechanism *n/a[115]
IS = ischemic stroke. SNP = single nucleotide polymorphism; * Association found via logistic regression analysis; n/a = not applicable.
Table
Table 3. MMP polymorphism relation to clinical outcome.
Table 3. MMP polymorphism relation to clinical outcome.
MMP StudiedPolymorphism StudiedGene RegionPopulation and/or LocationFindingTranscriptional ActivityReference
MMP-2-rs2241145 (G/C)IntronicPortugueseG-allele associated with improved clinical outcome *n/a[73]
MMP-2-rs1992116 (G/A)IntronicPortugueseG-allele associated with improved clinical outcome *n/a[73]
* Association found via logistic regression analysis; n/a = not applicable.
Table
Table 4. MMP Polymorphism relation to hemorrhagic transformation.
Table 4. MMP Polymorphism relation to hemorrhagic transformation.
MMP StudiedPolymorphism StudiedGene RegionPopulation and/or LocationFindingTranscriptional ActivityReference
MMP-9-1562 C/TPromoterChineseC-allele associated with higher rate of HTIncreased with C-allele[108]
MMP-9-1562 C/TPromoterMediterraneanNo differenceIncreased with C-allele[109]
HT = hemorrhagic transformation.

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Chang, J.J.; Stanfill, A.; Pourmotabbed, T. The Role of Matrix Metalloproteinase Polymorphisms in Ischemic Stroke. Int. J. Mol. Sci. 2016, 17, 1323. https://doi.org/10.3390/ijms17081323

AMA Style

Chang JJ, Stanfill A, Pourmotabbed T. The Role of Matrix Metalloproteinase Polymorphisms in Ischemic Stroke. International Journal of Molecular Sciences. 2016; 17(8):1323. https://doi.org/10.3390/ijms17081323

Chicago/Turabian Style

Chang, Jason J., Ansley Stanfill, and Tayebeh Pourmotabbed. 2016. "The Role of Matrix Metalloproteinase Polymorphisms in Ischemic Stroke" International Journal of Molecular Sciences 17, no. 8: 1323. https://doi.org/10.3390/ijms17081323

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