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)

Although ischemia remains the leading cause of acute renal failure in humans, there is little information on the expression and activities of gelatinases of kidney glomeruli during ischemia-reperfusion injury. In this study, we used a unilateral ischemia-reperfusion model to investigate the activity and expression of gelatinases in glomeruli during acute ischemia. Unilateral ischemia was induced in rats by vascular clamping (30 min) followed by reperfusion (60 min) and isolation of glomeruli. The activity and expression of gelatinase proteins were determined by gelatin zymography and Western blotting. Gelatinase mRNA levels were evaluated by reverse transcriptase-PCR. Ischemia and reperfusion increased serum creatinine levels, hallmark of acute renal failure. Ischemia induced mRNA and protein MMP-2 expression. There was strong stimulation of MMP-9 mRNA, both forms of dimeric MMP-9, and active monomeric MMP-9. In contrast to TIMP-1 decreasing, TIMP-2 protein and mRNA increased during ischemia. During reperfusion, there was a gradual reversal of the MMP-2 and MMP-9 levels and a strong inhibition of TIMP-1 and TIMP-2 at the protein and mRNA levels. Endocytic receptor LRP was increased during ischemia and returned to normal during reperfusion. Expression of MMP-9 docking receptor CD-44 was increased during reperfusion. Finally, ZO-1, an in vivo MMP-9 substrate, was degraded during ischemia, revealing that MMP-9 upregulated during ischemia was functional. Our data suggest that stimulation of gelatinase activity during ischemia could contribute to glomeruli injury, providing new therapeutic targets for acute renal failure in humans. In contrast, elevated monomeric MMP-9 activity due to TIMP-1 decrease during reperfusion may participate to glomerular recovery.
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PMID:Ischemia-reperfusion injury stimulates gelatinase expression and activity in kidney glomeruli. 1587 Aug 43

Although ischemia is the leading cause of acute renal failure in human, there is little information on the remodeling the kidney endothelium matrix during ischemic injury. In this study, we investigated the activity and expression of MMP-2 and MMP-9, in an isolated endothelial fraction following an acute in vivo reversible ischemia induced in rats by vascular clamping. Ischemia increased serum creatinine levels 1.4-fold, hallmark of acute renal failure. Isolation of the endothelial cell fraction was performed by affinity chromatography using an anti-PECAM-1 antibody. The isolated fraction was assessed by Western blotting analysis of endothelial cell markers. The positively selected fractions were enriched in the endothelial markers eNOS and PECAM-1 by 128-fold and 44-fold, respectively. Gelatin zymography showed that ischemia strongly stimulated proteolytic activity of proMMP-2 (1.8-fold), proMMP-9 (3-fold) and MMP-9 (4-fold) in the endothelial fractions. Western blot analysis indicated that TIMP-2 protein level increased by 3.2-fold in the endothelial fractions during ischemia. Surprisingly, TIMP-1 was absent from the endothelial preparations but was easily detected in the non-endothelial cells. Levels of the endocytic receptor LRP were increased by 2-fold during ischemia in the endothelial fractions. Occludin, a known in vivo MMP-9 substrate, was partly degraded in the endothelial fractions during ischemia, suggesting that the MMP-9 which was upregulated during ischemia was functional. These data suggest that ischemia in kidney could lead to the degradation of the vascular basement membrane and to increased permeability. This suggests new therapeutic approaches for ischemic pathologies by targeting MMP-9 and its regulators.
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PMID:Ischemia injury alters endothelial cell properties of kidney cortex: stimulation of MMP-9. 1611 9

Adverse outcome in bacterial meningitis is associated with the breakdown of the blood-brain barrier (BBB). Matrix-metalloproteinases (MMPs) facilitate this process by degradation of components of the BBB. This in turn results in acute complications of bacterial meningitis including edema formation, increased intracranial pressure and subsequent ischemia. We determined the parenchymal balance of MMP-9 and TIMP-1 (tissue inhibitor of MMP) and the structural integrity of the BBB in relation to cortical damage in an infant rat model of pneumococcal meningitis. The data demonstrate that the extent of cortical damage is significantly associated with parenchymal gelatinolytic activity and collagen type IV degradation. The increased gelatinolysis was found to be associated with a brain parenchymal imbalance of MMP-9/TIMP-1. These findings provide support to the concept that MMPs mediated disruption of the BBB contributes to the pathogenesis of bacterial meningitis and that protection of the vascular unit may have neuroprotective potential.
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PMID:In bacterial meningitis cortical brain damage is associated with changes in parenchymal MMP-9/TIMP-1 ratio and increased collagen type IV degradation. 1625 22

Omega-3 fatty acid therapy is a promising intervention for the secondary prevention of coronary artery disease (CAD). Omega-3 fatty acids have properties that promote atherosclerotic plaque stability and decrease the incidence of ischemia-driven cardiac arrhythmias. A large number of clinical trials conducted in patients with CAD or prior myocardial infarction (MI) have examined hard cardiovascular end points, including total mortality, cardiovascular mortality, sudden death, and nonfatal MI. Several intermediate cardiovascular end-point studies have also examined whether ventricular arrhythmias can be suppressed in patients with implantable cardioverter defibrillators (ICDs). Significant reductions in total mortality and sudden death--20% to 50%--have been found in studies using doses of 0.85 to 4.0 g/day, with treatment durations from 12 to 42 months. Favorable trends toward reduction in the incidence of arrhythmic events have been demonstrated in some, but not all, ICD studies. Omega-3 fatty acid therapy shows a general positive trend toward benefit in reducing life-threatening events after MI and in patients with ICDs who have ischemic arrhythmias. Results of the recent Japan EPA Lipid Intervention Study (JELIS) in a large cohort (N = 18,645) of Japanese men and women suggest significant benefits in the reduction of unstable angina and nonfatal coronary events. The totality of evidence supports a strong role for omega-3 fatty acids derived from fish oil in secondary prevention through a presumptive role as an antiarrhythmic agent and through an ability to promote plaque stabilization.
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PMID:Secondary prevention of coronary artery disease with omega-3 fatty acids. 1691 18

Many studies indicate that dietary omega-3 polyunsaturated fatty acids (PUFAs) have the cardioprotective properties. But majority of experiments were carried out with using omega-3 PUFAs from marine fish oil. The purpose of this study was to determine effects of the plant-derived omega-3 PUFA (alpha-linolenic acid (a-LA) on postischemic myocardial dysfunction, lipid peroxidation and antioxidant enzymes activity. Male Wistar rats (250-300 g) were divided into 4 groups (n = 10-12 each). In control group (1) were intact rats. The hearts from 2-nd group of animal were exposed to 20 min of global ischemia followed by 40 min reperfusion according to the Langendorff technique. The 3-rd and 4-th groups of animal received of the plant-derived oil (a-LA), which is a precursor of eicosapentaenoic acid and was used as a dietary supplement in dose 0.1 mg/kg per day for 4 weeks. The hearts from 4-th group of animal were also exposed to ischemia/ reperfusion. Analysis of myocardial phospholipid fatty acid content showed that consumption of the plant-derived 6-LA for 4 weeks changes fatty acid profile through incorporation of b-LA in cell membranes. It also reduced content of omega-6 PUFAs in membrane phospholipids. In 3-rd group content of a-LA and EPA were increased by 1.5- and 3.5-times, respectively, whereas content of AA was reduced by 1.7-times. The development of ischemia/ reperfusion in 2-nd group caused increase of free AA content in heart tissue by 3.5-times, whereas in 4-th group this increase was only by 1.4-time. Ischemia/reperfusion of the isolated rat heart in 4-th group was accompanied by reduced leukotriene C4 and thromboxane B2 production in 3-times and 1.9-times, respectively in comparison to 2-nd group. The time of myocardial function recovery after ischemia (heart rate, left ventricular development pressure), was shorter compare to 2-nd group. Also in 4th group end-diastolic pressure and coronary perfusion pressure during reperfusion period were significantly lower. Dietary omega-3 PUFAs resulted in remarkable decrease of reperfusion arrhythmias in 4-th group (in 3.8-times) and limited the oxidative stress through decrease free radical and lipid peroxidation production. In this group of animals the activity of antioxidant enzymes (superoxide dismutase and catalase) after ischemia/reperfusion were higher than in 2-nd group. We suggest that dietary supplement of the plant-derived alpha-LA for 4 weeks have cardioprotective effects similar to the effects of fish oil.
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PMID:[The effects of alpha-linolenic acid on the functioning of the isolated heart during acute myocardial ischemia/reperfusion]. 1717 34

Gene therapy may be a promising approach for treatment of brain ischemia. We and others previously demonstrated that increased activity of matrix metalloproteinases (MMPs) contributes to the tissue damage that results from ischemic injury. The proteolysis of MMPs is tightly controlled by tissue inhibitors of MMPs (TIMPs). In this study, we examined whether adenoviral-mediated gene transfer of TIMP-1 and TIMP-2 could protect against neuronal damage induced by global cerebral ischemia in mice. An adenovirus expressing TIMP-1 or TIMP-2 (AdTIMP-1 or AdTIMP-2) or a control adenovirus (RAd60) or vehicle was injected into the striatum 3 days before transient global cerebral ischemia. The extent of neuronal damage was quantified 3 days post-ischemia. There was no significant difference in the extent of neuronal damage in vehicle as compared to RAd60-treated mice. In contrast, neuronal damage was reduced, by approximately 50%, after gene transfer of AdTIMP-1 (P<0.001) and AdTIMP-2 (P< 0.01) as compared to controls. This study provides the first in vivo evidence of the protective effects of TIMP-1 and TIMP-2 via gene transfer in global ischemia.
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PMID:Neuroprotective effect of adenoviral-mediated gene transfer of TIMP-1 and -2 in ischemic brain injury. 1723 93

Oxidative stress secondary to ischemia can cause physiopathologic changes that adversely affect wound healing. In this experimental study, we hypothesized that the topical use of esterified glutathione, a well-known antioxidant, can minimize the effects of oxidative stress by an increase in intracellular glutathione and accelerate wound healing by increasing the contraction capacity of fibroblasts and preventing keratinocytes from apoptosis in a rat ischemic wound model. Experimental models were divided into 3 groups as treatment, control, and healthy. Bipedicled flaps were elevated from the dorsum of the rats, and 6-mm punch wounds were created at the end of the first day when the ischemia is most apparent. Wounds were followed histopathologically and immunohistochemically, and matrix metalloproteinase (MMP)-1 and tissue inhibitors of metalloproteinase (TIMP-1) levels were measured by ELISA. Samples were collected at 0, 5, 8, 10, and 12 days. Histopathologic evaluation revealed significant extracellular matrix deposition and reepithelization every fifth day in treatment and healthy groups when compared with control group. Immunohistochemical evaluation revealed increased apoptosis in basal keratinocytes in the control group when compared with the other groups. The evaluation of the samples collected at 5 and 8 days revealed increased MMP-1 levels in treatment and control groups, but the increase in TIMP-1 levels was more significant than MMP-1 levels in treatment group. MMP-1/TIMP-1 ratio was significantly low in the treatment group.Our results showed that topical GSH treatment can reduce oxidative stress, and the reestablishment of the MMP-1/TIMP-1 ratio gives way to adequate and regular extracellular matrix production and reepithelization. It is concluded that esterified GSH, which is experimentally shown to be effective in ischemic wound healing, can be used clinically in ischemic wounds.
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PMID:Effects of topical glutathione treatment in rat ischemic wound model. 1741 90

Polyunsaturated fatty acids (PUFAs) such as docosahexaenoic and eicosapentaenoic acids (DHA, EPA) exert ischemic anti-arrhythmic effects. However, their mechanism of action remains unknown. The present study was designed to investigate their potential effect on the regulation of the late sodium current as the basis for their ischemic anti-arrhythmic activity. Human isoforms of wild-type SCN5A and DeltaKPQ-mutated cardiac sodium channels were stably transfected in HEK 293 cells and, the resulting currents were recorded using the patch clamp technique in whole cell configuration. In addition to their effect to inhibit peak I(Na), acute application of DHA and EPA blocked veratridine-induced late sodium current (late I(Na-Verat)) in a concentration--dependent manner with IC(50) values of 2.1 +/- 0.5 microM and 5.2 +/- 0.8 microM,for DHA and EPA, respectively. Channels availability was reduced, resulting in a significant leftward shift of the steadystate inactivation curve by -10.0 +/- 2.1 mV and -8.5 +/- 0.2 mV for DHA and EPA, respectively. Similar inhibitory effects of DHA and EPA were also observed on late I(Na-KPQ). In addition to their role as blocking agents of peak I(Na), DHA and EPA reduced human late I(Na). These results could explain the antiarrhythmic properties of DHA and EPA during ischemia or following ischemia-reperfusion.
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PMID:Direct protective effects of poly-unsaturated fatty acids, DHA and EPA, against activation of cardiac late sodium current: a mechanism for ischemia selectivity. 1789 22

Enhanced matrix metalloproteinases (MMPs) can cause vasogenic edema and hemorrhagic transformation after cerebral ischemia, and affect the extent of ischemic injury. We hypothesized that the endogenous MMP inhibitors, tissue inhibitor of MMPs (TIMPs), were essential to protect against blood-brain barrier (BBB) disruption after ischemia by regulating the activities of MMPs. We confirmed the transition of MMP-2 and MMP-9, and the TIMPs family after 30 mins of middle cerebral artery occlusion, and elucidated the function of TIMP-1 and TIMP-2 in focal ischemia, using TIMP-1(-/-) and TIMP-2(-/-) mice. TIMP-1 mRNA expression was gradually increased until 24 h after reperfusion. In TIMP-1(-/-) mice, MMP-9 protein expression and gelatinolytic activity were significantly more augmented after cerebral ischemia than those in WT mice, and were accompanied by exacerbated BBB disruption, neuronal apoptosis, and ischemic injury. In contrast, TIMP-2 gene deletion mice exhibited no significant difference in MMP expressions and the degree of ischemic injury despite an increased Evans blue leakage. These results suggest that TIMP-1 inhibits MMP-9 activity and can play a neuroprotective role in cerebral ischemia.
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PMID:Tissue inhibitor of metalloproteinases protect blood-brain barrier disruption in focal cerebral ischemia. 1856 Apr 39

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


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