Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Erythropoietin (Epo) was recently defined as an endogenous agent with more than hematopoietic functions. Previously we explored the potential of this agent to ameliorate lung ischemia-reperfusion (I/R) injury. The present study aims to determine the optimal dose and timing of administration for improving lung injury, and to further investigate the mechanisms by which Epo ameliorates lung I/R injury. The left lungs of Sprague-Dawley rats underwent 90 min ischemia and 120 min reperfusion. Firstly, animals in different groups were intraperitoneally injected with various doses of recombined human erythropoietin (rhEpo) 24 h prior to operation, 2 h prior to operation, or after the onset of reperfusion. Pulmonary myeloperoxidase (MPO) activity and malondialdehyde (MDA) content were evaluated. Treatment with 3 KU/kg rhEpo 2 h prior to operation was optimal for attenuating pulmonary MPO activity and MDA content. With such treatment, ultrastructural changes of pneumocytes were observed, and the pneumocyte apoptosis index was also determined by terminal dUTP nick-end labeling method. The plasma concentrations of tumor necrosis factor (TNF)-alpha and matrix metalloproteinase (MMP)-9 were evaluated by enzyme-linked immunosorbent assay, and pulmonary expression by immunohistochemistry. When pretreated with rhEpo, the pneumocyte ultrastructure was predominantly maintained and the pulmonary apoptosis index was markedly reduced. In comparison with untreated animals, in treated animals the plasma concentrations of TNF-alpha and MMP-9 were significantly decreased, and their expression in lung tissue was markedly reduced as well. The results indicated that Epo potently protected against lung I/R injury by inhibiting systemic and local expression of TNF-alpha and MMP-9.
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PMID:Erythropoietin attenuates ischemia-reperfusion induced lung injury by inhibiting tumor necrosis factor-alpha and matrix metalloproteinase-9 expression. 1906 83

Magnetic resonance imaging (MRI) findings of large white matter hyperintensities (LWMH), decreased brain volume and silent cerebral infarcts (SCI) are subclinical indices of brain ischemia and aging. Although the pathophysiology of these findings remains uncertain, extracellular matrix (ECM) remodeling, a process regulated by matrix metalloproteinases (MMPs) and their inhibitors (TIMPs), may be implicated. We evaluated the cross-sectional relations of circulating MMP-9 and TIMP-1 to these MRI indices in 583 stroke and dementia-free, Framingham Offspring participants (mean age 57 years, 58% women). Using multivariable regression MMP-9 (detectable versus non-detectable) and TIMP-1 (modeled as sex-specific quartiles) were related to LWMH (>1S.D. above age-specific mean; yes/no), SCI (yes/no) and total brain volume (ratio of parenchymal to intracranial volume, TCBVr). Mean TCBVr was 0.78 (S.D. 0.03), 13% of subjects had LWMH and 12% had SCI. Detectable MMP-9 was associated with higher prevalence of LWMH (OR 2.09, 95%confidence interval (CI) 1.00-4.37), but not with TCBVr. TIMP-1 was associated with a high prevalence of LWMH (OR for Q4 versus Q1-3: 1.83, 95%CI 1.06-3.18) and with lower mean TCBVr (Q4 associated with 0.17 S.D. units lower value relative to Q1-3; p=0.04). Neither biomarker was associated with SCI. Our findings are preliminary but if confirmed in further studies, suggest a pathophysiological role for the MMP/TIMP pathway in processes of brain ischemia and aging.
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PMID:Association of matrix metalloproteinases with MRI indices of brain ischemia and aging. 1912 58

Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, has shown protective effects against ischemic insult in various tissues. Pioglitazone is also reported to reduce matrix metalloproteinase (MMP) activity. MMPs can remodel extracellular matrix components in many pathological conditions. The current study was designed to investigate whether the neuroprotection of pioglitazone is related to its MMP inhibition in focal cerebral ischemia. Mice were subjected to 90 min focal ischemia and reperfusion. In gel zymography, pioglitazone reduced the upregulation of active form of MMP-9 after ischemia. In in situ zymograms, pioglitazone also reduced the gelatinase activity induced by ischemia. After co-incubation with pioglitazone, in situ gelatinase activity was directly reduced. Pioglitazone reduced the infarct volume significantly compared with controls. These results demonstrate that pioglitazone may reduce MMP-9 activity and neuronal damage following focal ischemia. The reduction of MMP-9 activity may have a possible therapeutic effect for the management of brain injury after focal ischemia.
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PMID:PPARgamma agonist pioglitazone reduces matrix metalloproteinase-9 activity and neuronal damage after focal cerebral ischemia. 1913 26

There is evidence that statin treatment before ischemia protects myocardium from ischemia/reperfusion injury. The objective is to determine whether rosuvastatin administered during reperfusion modifies infarct size and the recovery of postischemic ventricular dysfunction in normocholesterolemic and hypercholesterolemic rabbits. In addition, we also evaluated the role of matrix metalloproteinase type 2 (MMP)-2 activation. Langendorff-perfused rabbit hearts were subjected to 30 minutes of ischemia and 120 minutes of reperfusion. In group 2, we added rosuvastatin after 30 minutes of ischemia and from the beginning of reperfusion. In group 3, an MMP inhibitor (doxycycline) was administered during the first 2 minutes of reperfusion. Finally, we repeated these groups but in hypercholesterolemic rabbits (groups 4, 5, and 6). The infarct size was 16.6% +/- 3.9% in group 1 and 25.6% +/- 2.7% in group 4. Rosuvastatin reduced infarct size to 4.5% +/- 1.1% and 6.1% +/- 1.5% in groups 2 and 5, respectively (P < 0.05). Rosuvastatin significantly decreased MMP-2 activity during reperfusion, and doxycycline induced an inhibition of MMP-2 activity and a reduction of infarct size in normocholesterolemic (4.9% +/- 0.9%) and hypercholesterolemic animals (8.3% +/- 1.6%) (P < 0.05). Rosuvastatin reduces infarct size and attenuates MMP-2 activity. These data and the correlation between MMP-2 and infarct size suggest that MMP-2 plays an important role in the mechanisms of cardioprotection afforded by rosuvastatin.
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PMID:Rosuvastatin given during reperfusion decreases infarct size and inhibits matrix metalloproteinase-2 activity in normocholesterolemic and hypercholesterolemic rabbits. 1918 35

Doxycycline, a tetracycline antibiotic inhibits matrix metalloproteinase (MMP) and reduces neuronal damage in focal brain ischemia. This study was undertaken to assess if doxycycline reduces delayed neuronal damage following transient global cerebral ischemia through MMP inhibition. C57BL/6 mice were subjected to 20 min global cerebral ischemia. Doxycycline was administered to mice 30 min before and 2 h after ischemia. In TUNEL assay, damaged neurons were also apparent in the CA1 and CA2 areas and doxycycline reduced TUNEL-positive neurons. Gelatin gel and in situ zymography showed upregulation of gelatinase activity after ischemia. Doxycycline significantly inhibited MMP-9 activity in gel zymography and also suppressed in situ gelatinase activity. Laminin degradation was remarkable in CA1 and CA2 areas after ischemia and doxycycline reduced the laminin degradation and neuronal loss. Our data suggest that doxycycline may provide a neuroprotection against global cerebral ischemia since it reduces perineuronal laminin degradation by inhibiting MMP-9 activity.
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PMID:Doxycycline inhibits matrix metalloproteinase-9 and laminin degradation after transient global cerebral ischemia. 1920 Aug 54

Endothelin-1 (ET-1) is up-regulated in the endothelial cells and astrocytes under ischemia. Transgenic mice with astrocytic ET-1 over-expression (GET-1) showed more severe neurological deficit and larger infarct after transient middle cerebral artery occlusion (MCAO). Here, the significance of endothelial ET-1 in ischemic brain injury was investigated using transgenic mice with the endothelial ET-1 over-expression (TET-1). Increased ET-1 level was observed in the TET-1 brain infarct core after transient MCAO. ET(A) receptor expression was induced in the penumbra and ET(A) antagonist (A-147627) partially normalized the infarct volume and neurological deficit. In the infarct core of TET-1 brain, superoxide, nitrotyrosine, and gp91(phox) levels were increased. TET-1 brain displayed increased matrix metalloproteinase-2 expression, water content, immunoglobulin leakage and decreased occludin level in the ipsilateral hemisphere indicative of BBB breakdown and hemispheric edema. Interestingly, AQP-4 expression was increased in the penumbra of TET-1 brain following transient MCAO leading to the water accumulation. Taken together, endothelial ET-1 over-expression and ETA receptor activation contributes to the increased oxidative stress, water accumulation and BBB breakdown after transient MCAO leading to more severe neurological deficit and increased infarct.
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PMID:Endothelial endothelin-1 over-expression using receptor tyrosine kinase tie-1 promoter leads to more severe vascular permeability and blood brain barrier breakdown after transient middle cerebral artery occlusion. 1923 Aug 25

CD47 is a cell surface glycoprotein that helps mediate neutrophil transmigration across blood vessels. The present study was performed to determine whether absence of the CD47 gene decreases focal ischemic brain damage. Mice were subjected to 90 min middle cerebral artery occlusion. CD47 knockout mice were compared against matching wildtype mice. CD47 expression was checked by Western blotting. Infarct volume and ischemic brain swelling were quantified with cresyl violet-stained brain sections at 24 and 72 h after ischemia. The tight junction protein claudin-5 was detected by imunohistochemistry. Two surrogate markers of neuroinflammation, brain levels of matrix metalloproteinase-9 (MMP-9) and infiltration of neutrophils, were assessed by immunohistochemistry. Western blots confirmed that CD47 was absent in knockout brains. Ischemia did not appear to upregulate total brain levels of CD47 in WT mice. In CD47 knockout mice, infarct volumes were reduced at 24 and 72 h after ischemia, and hemispheric swelling was decreased at 72 h. Loss of claudin-5 was observed in ischemic WT brain. This effect was ameliorated in CD47 knockout brains. Extravasation of neutrophils into the brain parenchyma was significantly reduced in CD47 knockout mice compared to wildtype mice. MMP-9 appeared to be upregulated in microvessels within ischemic brain. MMP-9 levels were markedly lower in CD47 knockout brains compared to wildtype brains. We conclude that CD47 is broadly involved in neuroinflammation, and this integrin-associated-protein plays a role in promoting MMP-9 upregulaton, neutrophil extravasation, brain swelling and progression of acute ischemic brain injury.
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PMID:CD47 gene knockout protects against transient focal cerebral ischemia in mice. 1923 73

The purpose of this study was to evaluate the ability of novel semiselective matrix metalloproteinase inhibitors (MMPI) to protect myocardial structure-function in the setting of ischemia-reperfusion injury. For this purpose, an isolated rat model of myocardial stunning and infarction was used. Isolated hearts were subjected to 20-30 minutes of global no-flow ischemia and 30-minute reperfusion. Myocardial performance was assessed as the product of the heart rate and left ventricular developed pressure (rate-pressure product, RPP). Coronary flow rates, ventricular weights, indicators of muscle (troponin I), and fibrillar collagen damage (collagen opalation) were measured. Four MMPI were tested: 2 non-hydroxamate, semiselective inhibitors (PY-2 and 1,2-HOPO-2) and 2 broad-spectrum inhibitors (PD166793 and CGS27023A). The non-hydroxamate, semiselective inhibitors were shown to be nontoxic in cocultures of cardiac cells. Results indicate that semiselective inhibitors (in particular 1,2-HOPO-2) yield improved cardiac performance (approximately 23% higher RPP vs. controls) and coronary flow rates (approximately 22%), reducing muscle (approximately 25%) and fibrillar collagen damage (approximately 60%). Evidence suggests the involvement of matrix metalloproteinase-2 in these actions. Interestingly, broad-spectrum inhibitors only show modest improvement (approximately 8% higher RPP vs. controls) without affecting the other measured parameters. In conclusion, semiselective MMPI can act as cardioprotectors in isolated perfused rat hearts. Protection is observed in all structural components of the myocardium translating into improved contractile function. Based on these findings, non-hydroxamate, semiselective MMPI warrant further studies as to their ability to protect ischemic myocardium in the in vivo setting.
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PMID:Effects of novel semiselective matrix metalloproteinase inhibitors on ex vivo cardiac structure-function. 1936 78

Active and passive tobacco smoke are associated with the dysfunction of endothelial physiology and vascular impairment. Studies correlating the effects of smoking and the brain microvasculature at the blood-brain barrier (BBB) level have been largely limited to few selective compounds that are present in the tobacco smoke (TS) yet the pathophysiology of smoking has not been unveiled. For this purpose, we characterized the physiological response of isolated human brain microvascular endothelial cells (HBMEC) and monocytes to the exposure of whole soluble TS extract. With the use of a well established humanized flow-based in vitro blood-brain barrier model (DIV-BBB) we have also investigated the BBB physiological response to TS under both normal and impaired hemodynamic conditions simulating ischemia. Our results showed that TS selectively decreased endothelial viability only at very high concentrations while not significantly affecting that of astrocytes and monocytes. At lower concentrations, despite the absence of cytotoxicity, TS induced a strong vascular pro-inflammatory response. This included the upregulation of endothelial pro-inflammatory genes, a significant increase of the levels of pro-inflammatory cytokines, activated matrix metalloproteinase, and the differentiation of monocytes into macrophages. When flow-cessation/reperfusion was paired with TS exposure, the inflammatory response and the loss of BBB viability were significantly increased in comparison to sham-smoke condition. In conclusion, TS is a strong vascular inflammatory primer that can facilitate the loss of BBB function and viability in pathological settings involving a local transient loss of cerebral blood flow such as during ischemic insults.
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PMID:Tobacco smoke: a critical etiological factor for vascular impairment at the blood-brain barrier. 1953 13

Disruption of the integrity of the blood-brain barrier (BBB) is an important mechanism of cerebrovascular diseases, including neonatal cerebral hypoxia-ischemia (HI). Although both tissue-type plasminogen activator (tPA) and matrix metalloproteinase-9 (MMP-9) can produce BBB damage, their relationship in neonatal cerebral HI is unclear. Here we use a rodent model to test whether the plasminogen activator (PA) system is critical for MMP-9 activation and HI-induced brain injury in newborns. To test this hypothesis, we examined the therapeutic effect of intracerebroventricular injection of plasminogen activator inhibitor-1 (PAI-1) in rat pups subjected to unilateral carotid artery occlusion and systemic hypoxia. We found that the injection of PAI-1 greatly reduced the activity of both tPA and urokinase-type plasminogen activator after HI. It also blocked HI-induced MMP-9 activation and BBB permeability at 24 h of recovery. Furthermore, magnetic resonance imaging and histological analysis showed the PAI-1 treatment reduced brain edema, axonal degeneration, and cortical cell death at 24-48 h of recovery. Finally, the PAI-1 therapy provided a dose-dependent decrease of brain tissue loss at 7 d of recovery, with the therapeutic window at 4 h after the HI insult. Together, these results suggest that the brain PA system plays a pivotal role in neonatal cerebral HI and may be a promising therapeutic target in infants suffering hypoxic-ischemic encephalopathy.
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PMID:Therapeutic administration of plasminogen activator inhibitor-1 prevents hypoxic-ischemic brain injury in newborns. 1958 73


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