Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple sclerosis (MS) and stroke pathology are characterized blood-brain barrier breakdown, leucocyte emigration, and tissue destruction. Each process is thought to involve the matrix metalloproteinases (MMP), but little is known of their expression. We undertook to investigate whether MMP expression is dependent on the nature of the CNS lesion and whether expression would coincide with the histopathology. MS or cerebral-infarct tissue was examined for the presence of gelatinase-A, gelatinase-B, matrilysin and stromelysin-1. Gelatinases A and B and matrilysin expression was found to be up-regulated in microglia/macrophages within acute MS lesions. In active-chronic MS lesions, matrilysin and gelatinase-A expression was pronounced in the active borders. In chronic MS lesions, the expression of matrilysin was confined to macrophages within perivascular cuffs. The pattern of MMP expression in infarct lesions differed considerably. Gelatinase-B was strongly expressed by neutrophils in tissue from patients up to 1 week after an infarct, whereas gelatinase-A and matrilysin staining was much less marked. From 1 week to 5 years, neutrophils were absent and the large number of macrophages present were expressing matrilysin and gelatinase A. Only a low level of gelatinase-A and matrilysin expression was observed in normal brain controls. Thus, MMPs are expressed in inflammatory lesions in the CNS, but their individual expression is dependent on the nature and chronicity of the lesion. However, the general pattern of expression, in perivascular cuffs and in active lesions, supports a role for these enzymes as mediators of blood-brain barrier breakdown and tissue destruction, both in MS and in cerebral ischaemia.
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PMID:Differential matrix metalloproteinase expression in cases of multiple sclerosis and stroke. 936 66

This study hypothesizes that endothelin-1 induces renal damage by increasing expression of growth/inflammatory factors, important in renal fibrosis. Male stroke-prone spontaneously hypertensive rats (SHRSPs) (8-weeks, n = 24) were randomized into three groups: control group, high-salt group (4% NaCl), and salt plus an endothelin A receptor antagonist, BMS 182874 (40 mg/kg/d). After 20 weeks treatment, rats were killed. Messenger RNA (mRNA) expression of renal preproendothelin-1, endothelin A and B receptors, and procollagen I and III was evaluated by reverse transcription polymerase chain reaction. Expression of transforming growth factor (TGF)-beta1 and basic fibroblast growth factor (bFGF) was determined by immunoblotting. Matrix metalloproteinase-2 (MMP-2) activity was measured by zymography. In salt-loaded SHRSPs, preproendothelin-1 mRNA expression was increased 1.6-fold, and endothelin A receptor mRNA expression was decreased (70% of control). Salt-loaded SHRSPs had increased renal expression of TGF-b1 and procollagens. MMP-2 activity was augmented fivefold. BMS decreased (p < 0.01) expression of TGF-beta1, bFGF, and procollagen I and reduced MMP-2 activity. Thus severe hypertension and renal dysfunction in salt-loaded SHRSPs are associated with increased expression of renal endothelin-1, growth factors, and collagen. BMS treatment alleviated these effects, suggesting that nephroprotection by endothelin A receptor blockade is mediated by normalizing expression of growth factors, reducing extracellular matrix deposition, and decreasing MMP activity.
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PMID:Endothelin A receptor blockade decreases expression of growth factors and collagen and improves matrix metalloproteinase-2 activity in kidneys from stroke-prone spontaneously hypertensive rats. 1202 84

Cerebral amyloid angiopathy (CAA) is a major pathological feature of Alzheimer's disease and related disorders. Human cerebrovascular smooth muscle (HCSM) cells, which are intimately associated with CAA, have been used as an in vitro model system to investigate pathologic interactions with amyloid beta protein (A beta). Previously we have shown that pathogenic forms of A beta induce several pathologic responses in HCSM cells including fibril assembly at the cell surface, increase in the levels of A beta precursor, and apoptotic cell death. Here we show that pathogenic A beta stimulates the expression and activation of matrix metalloproteinase-2 (MMP-2). Furthermore, we demonstrate that the increase in MMP-2 activation is largely caused by increased expression of membrane type-1 (MT1)-MMP expression, the primary MMP-2 activator. Finally, treatment with MMP-2 inhibitors resulted in increased HCSM cell viability in the presence of pathogenic A beta. Our findings suggest that increased expression and activation of MMP-2 may contribute to HCSM cell death in response to pathogenic A beta. In addition, these activities may also contribute to loss of vessel wall integrity in CAA resulting in hemorrhagic stroke. Therefore, further understanding into the role of MMPs in HCSM cell degeneration may facilitate designing therapeutic strategies to treat CAA found in AD and related disorders.
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PMID:Pathogenic A beta induces the expression and activation of matrix metalloproteinase-2 in human cerebrovascular smooth muscle cells. 1275 80

Stroke is the third leading cause of death and the leading cause of permanent disability in western countries and the incidence of stroke is expected to increase in the foreseeable future due to the ageing population. The effective treatment of stroke remains challenging due to the complexity and heterogenicity of the disease. Recombinant tissue plasminogen activator (rt-PA) is the only FDA-approved therapy for stroke during the first 3 hr after the disease onset. However the risk of hemorrhage and its narrow therapeutic window has limited its use in clinic. Inflammation has been known to play a crucial role in the induction and development of stroke and tumor necrosis factor-alpha (TNF-alpha) is a central player in the initiation of multiple inflammatory cascades. The recent success of three anti-TNF biologics in the clinic for the treatment of rheumatoid arthritis as well as other inflammatory diseases has further validated TNF159nflammation. TNF-alpha has also been shown to be associated with ischemic stroke. Anti-TNF biologics have been shown to be effective in reducing the disease symptoms in various pre-clinical stroke models. Small molecule TNF inhibitors are highly desirable due to the limitations of protein therapeutics. Tumor necrosis factor-alpha-converting enzyme (TACE) is the major sheddase of TNF-alpha and is essential for the generation of soluble, mature TNF-alpha. Thus TACE appears to be an attractive target for development of oral small molecule TNF-alpha inhibitors. This review summarizes the role of TNF-alpha in stroke and the effect of several TACE/MMP inhibitors in pre-clinical stroke models. The data strongly suggest that TACE/MMP inhibitors have great therapeutic potential and may be valuable alternatives in treating stroke in the clinic.
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PMID:Therapeutic potential of TACE inhibitors in stroke. 1585 1

MMPs play an important role in ischemic and hemorrhagic stroke. We analyzed replicate serum samples from 20 normal healthy individuals to assess reproducibility of MMP determinations, and found that MMP-2 and MMP-9 determinations were quite consistent. We then studied the serum levels of MMP-2 and MMP-9 in patients suffering from subarachnoid hemorrhage (SAH), another stroke subtype. Serum MMP-2 and MMP-9 levels from SAH patients were measured sequentially using gelatine zymography in 11 patients after acute SAH. The occurrence of intracerebral aneurysms and vasospasms and the initial Hunt and Hess score were analysed in relation to MMP-levels. MMP-2 levels are significantly decreased while MMP-9 levels are increased in SAH patients relative to controls. MMP-2 levels remain depressed out to day 12 post SAH, but MMP-9 levels may recover by day 12.
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PMID:MMP-2 and MMP-9 levels in peripheral blood after subarachnoid hemorrhage. 1708 71

Local environmental conditions contribute to the activation state of cells. Extracellular matrix glycoproteins participate in cell-cell boundaries within the microvascular and extravascular tissues of the central nervous system and provide a scaffold for the local environment. These conditions are altered during focal cerebral ischemia (and other central nervous system disorders) when extracellular matrix boundaries are degraded or when matrix proteins in the vascular circulation enter the neuropil as the microvascular permeability barrier is degraded. Microglia in the resting state become activated after the onset of ischemia. During activation these cells can express a number of factors and proteases, including latent matrix metalloproteinase-9 (pro-MMP-9). Whereas MMP-9 and MMP-2 are generated early during focal ischemia in select models, their cellular sources in vivo are still under study. In vitro microglia cells activate and respond to exposure to specific matrix proteins (eg, vitronectin, fibronectin) that circulate. Certain MMP inhibitors, specifically tetracycline derivatives, can modulate microglial activation and reduce injury volume in limited studies. But, the injury reduction relies on preinjury exposure to the tetracycline. Other studies underway suggest the hypothesis that microglial cell activation and pro-MMP-9 generation during focal cerebral ischemia is promoted in part by matrix proteins in the circulation that extravasate into the neuropil when the blood-brain barrier is compromised. These matrix proteins are known to activate microglia through their specific cell surface matrix receptors.
Stroke 2007 Feb
PMID:Microglial activation and matrix protease generation during focal cerebral ischemia. 1726 8

Generation of thrombin is associated with vascular remodeling that involves proliferation of vascular smooth muscle cells (SMCs) and activation of pro-matrix metalloproteinases (pro-MMPs). The present study was to investigate whether thrombin would induce mitogenesis and activation of pro-MMPs in cerebrovascular SMCs (CSMCs), and if so, whether MMP activity would contribute to the CSMC mitogenesis. CSMCs were cultured from pig middle cerebral arteries and stimulated with thrombin. Thrombin (0.1-5U/ml), in a dose-dependent fashion, stimulated mitogenesis in CSMCs as detected by bromo-2'-deoxy-uridine (BrdU) incorporation. Additionally, zymographic analyses showed that thrombin stimulated the appearance of the active form of MMP-2 (MMP-2) in a concentration-dependent manner, but not the release of pro-MMP-2. Thrombin did not affect expression of cell-associated pro-MMP-2 protein as evaluated by Western blot analysis. Treatment with the synthetic MMP inhibitor GM6001 or antibodies to MMP-2 significantly reduced thrombin-induced BrdU incorporation in CSMCs. In conclusion, thrombin activates pro-MMP-2 in the absence of elevated pro-MMP-2 expression and secretion in CSMCs, and thrombin induces CSMC mitogenesis involving its action on MMP-2. These findings suggest that thrombin may have relevance in cerebrovascular remodeling associated with brain atherosclerosis and atherothrombotic ischemic stroke through a mechanism involving MMP-dependent CSMC mitogenesis.
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PMID:Thrombin stimulates mitogenesis in pig cerebrovascular smooth muscle cells involving activation of pro-matrix metalloproteinase-2. 1915 Mar 92

Treatment of carotid artery stenosis by endarterectomy or stenting can significantly reduce stroke risk. In clinical practice, indication for surgery or stenting is primarily based on the degree of stenosis, but there is growing awareness that pathophysiological features within a vulnerable plaque play a key role in predicting stroke risk. Important molecular processes associated with plaque vulnerability are inflammation, lipid accumulation, proteolysis, apoptosis, angiogenesis and thrombosis. The rapidly emerging field of molecular and functional imaging strategies allows identification of pathophysiological processes in carotid artery stenosis. We aimed to review the literature regarding the current most promising advanced imaging techniques in carotid artery disease. Various advanced imaging methods are available, such as high-resolution magnetic resonance imaging (HR-MRI), single photon emission computed tomography (SPECT), positron emission tomography (PET) and near-infrared fluorescence (NIRF). Radionuclide and fluorescent tracers that identify inflammation, apoptosis and proteolysis, such as FDG, MMP probes and Annexin A5, are promising. A combination of activity of molecular processes and detailed anatomic information can be obtained, providing a powerful tool in the identification of the vulnerable plaque. With these developments, we are entering a new era of imaging techniques in the selection of patients for carotid surgery.
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PMID:Advanced carotid plaque imaging. 2041 23

The metalloproteinases (MMPs, matrixins) are zinc-containing endopeptidases involved in the metabolism of extracellular matrix as well as in the cleavage of other proteins. The MMP family currently consists of 28 enzymes with somewhat different activities. The members are in part categorized into groups according to either structure or preferred substrates and referred to as collagenases, gelatinases, stromelysins, matrilysins, and membrane-bound MMPs. The proteinase activities exerted by 11 of the 28 MMPs have been implicated in some of the biologic processes associated with atherosclerosis and its ischemic clinical manifestations such as myocardial infarction and stroke. For example, several of the MMPs are locally expressed within human atherosclerotic lesions. However, association studies of subclinical atherosclerosis have generated contradictory results in the role of MMP activities. In addition, circulating MMP levels as well as genetic variations within the genes encoding the different enzymes have been associated with both an increased and decreased cardiovascular risk. Finally, experimental studies of hyperlipemic mice and vascular injury have suggested some of the MMPs function as modulators of atherogenesis, vascular remodeling, and plaque rupture.
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PMID:Matrix metalloproteinases in atherothrombosis. 2022 59

Previous studies indicate that tau protein, a marker of damage to neurons, is present in the serum of healthy patients at a concentration approximately 40 percent that of patients with ischemic stroke We assumed that increased serum activity of gelatinases (matrix metalloproteinase [MMP]-2 and MMP-9) can influence the level of tau protein in serum, probably due to disruption of the blood-brain barrier. We obtained blood sera from 31 patients admitted within the first 24 hours of ischemic stroke on days 1, 5 and 10, following the onset of stroke. Tau protein was detected in the serum of 12 patients (38.7 percent). The highest MMP-9 activity was recorded on day 5 (p < 0.05). Serum gelatinase activity did not differ between tau protein-positive or -negative individuals. However, a high degree of correlation between mean MMP-9 activity and the maximum tau protein level was observed for patients with detectable tau protein (r = 0.71, p = 0.009). Our study suggests that MMP-9 can increase the tau protein level in the sera of patients during acute ischemic stroke.
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PMID:Matrix metalloproteinase-9 contributes to the increase of tau protein in serum during acute ischemic stroke. 2062 31


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