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 has been shown to disrupt cell adhesion, the underlying molecular mechanism is unknown. In these studies, we adapted a model of ischemia-reperfusion to normal rat kidney (NRK) cells, examined disruption of the cadherin/catenin complex, and identified a role for matrix metalloproteinases (MMPs) in ischemia-induced cleavage of cadherins. In NRK cells, ischemia was induced by applying a thin layer of PBS solution supplemented with calcium and magnesium and a layer of mineral oil, which restricts exposure to oxygen. NRK cells exhibited extracellular 80-kDa and intracellular 40-kDa E-cadherin fragments after 4 h of ischemia, and at 6 h the expression of full-length E-cadherin decreased. While no fragments of N-cadherin, alpha-catenin, and gamma-catenin were observed at any time point, the detectable levels of these proteins decreased during ischemia. Ischemia was detected by an increase in pimonidazole adducts, as well as an increase in glucose transporter-1 protein expression. Ischemia did not decrease cell number, but there was a decrease in ATP levels. In addition, there was no evidence of cleaved caspase 3 or 9 during 6 h of ischemia. The MMP inhibitors GM-6001 and TAPI-O inhibited cleavage and/or loss of E- and N-cadherin protein expression. Tissue inhibitors of metalloproteinases (TIMP)-3 and to a lesser extent TIMP-2, but not TIMP-1, inhibit ischemic cleavage and/or loss of E- and N-cadherin. These results demonstrate that ischemia induces a selective metalloproteinase-dependent cleavage of E-cadherin and decrease in N-cadherin that are associated with a disruption of junctional contacts.
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PMID:Ischemia-induced cleavage of cadherins in NRK cells: evidence for a role of metalloproteinases. 1576 36

Following cardiopulmonary bypass (CPB) and cardiac global ischemia and reperfusion, proinflammatory genes are up-regulated, and nuclear factor (NF)-kappaB is involved in this regulation. We studied whether inactivation of NF-kappaB could decrease myocardial ischemia/reperfusion injury with cardioplegia during CPB, attenuate matrix metalloproteinase (MMP) activation, and prevent cardiac mechanical dysfunction. Rabbits received normal saline (group 1) or curcumin (70 and 7 micromol/kg in groups 2 and 3) injection 2 hours before CPB. Total CPB was initiated, and myocardial protection was delivered every 20 minutes for 60 minutes of cardiac arrest. Rabbits were weaned from CPB and reperfused for 4 hours before the hearts were harvested. Blood was sampled at various time points. Postoperative expression of myocardial mRNA levels of interleukin 6, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha, postreperfusion plasma level of troponin I, and cardiac mechanical dysfunction were significantly decreased in the curcumin groups. The myocardial levels of activated MMP-2 and -9 were also significantly reduced compared with the control group. In conclusion, by inhibiting NF-kappaB activation, the up-regulation of cardiac proinflammatory genes can be ameliorated, and the activation of MMPs can be decreased during CPB, thereby lessening severity of cardiac mechanical dysfunction after global cardiac ischemia/reperfusion injury.
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PMID:Inhibition of NF-kappa B activation can attenuate ischemia/reperfusion-induced contractility impairment via decreasing cardiomyocytic proinflammatory gene up-regulation and matrix metalloproteinase expression. 1577 17

After cerebral ischemia, angiogenesis, by supplying for the deficient perfusion, may be a beneficial process for limiting neuronal death and promoting tissue repair. In this study, we showed that the combination of Ang-1 and vascular endothelial growth factor (VEGF) provides a more adapted therapeutic strategy than the use of VEGF alone. Indeed, we showed on a focal ischemia model that an early administration of VEGF exacerbates ischemic damage, because of its effects on blood-brain barrier (BBB) permeability. In contrast, a coapplication of Ang-1 and VEGF leads to a significant reduction of the ischemic and edema volumes by 50% and 42%, respectively, in comparison with VEGF-treated mice. We proposed that Ang-1 blocks the BBB permeability effect of VEGF in association with a modulation of matrix metalloproteinase (MMP) activity. Indeed, we showed on both ischemic in vivo and BBB in vitro models that VEGF enhances BBB damage and MMP-9 activity and that Ang-1 counteracts both effects. However, we also showed a synergic angiogenic effect of Ang-1 and VEGF in the brain. Taken together, these results allow to propose that, in cerebral ischemia, the combination of Ang-1 and VEGF could be used early to promote the formation of mature neovessels without inducing side effects on BBB permeability.
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PMID:VEGF-induced BBB permeability is associated with an MMP-9 activity increase in cerebral ischemia: both effects decreased by Ang-1. 1590 95

Vascular endothelial growth factor (VEGF) is a unique growth factor associated with angiogenesis, vascular permeability, and neuroprotection. The aim of this study was to observe the effects of early intraarterial infusion of low-dose VEGF on ischemia/reperfusion injury after transient focal cerebral ischemia in rats. Male Sprague-Dawley rats were subjected to 2 h of focal ischemia by middle cerebral artery occlusion. After the 2 h ischemia, the rats were infused with 0.3 microg/kg of VEGF (n = 15), or the vehicle as a control (n = 15), via the reperfused internal carotid artery. The brains were collected after a 1 h, 6 h, or 72 h reperfused period. Severity of ischemic cellular injury, serum extravasation, hemorrhagic transformation, and matrix metalloproteinase (MMP)-2 and -9 expressions were compared between the VEGF-treated and control groups. No significant difference in the extent of ischemic cellular injury and serum extravasation was observed between the two groups. However, vessel numbers with hemorrhagic transformation were significantly greater in the VEGF-treated group than in the control group after the 72 h reperfusion (9.4 +/- 1.6 versus 2.6 +/- 1.5; P = 0.028). The severity of hemorrhagic transformation was not correlated with the extent of ischemic cellular injury or serum extravasation. MMP-2 and -9 expressions were not enhanced in the VEGF-treated group compared with the control group. These results suggest that exogenous VEGF administered intravascularly at a very early point in reperfusion aggravates hemorrhagic transformation. The aggravated hemorrhagic transformation does not seem to depend on the enlargement of ischemic cellular injury, serum extravasation, or overexpressions of MMP-2 and -9.
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PMID:Aggravation of hemorrhagic transformation by early intraarterial infusion of low-dose vascular endothelial growth factor after transient focal cerebral ischemia in rats. 1593 98

(1) Cerebral ischemia and reperfusion induce several changes on the endothelial cells at the microcirculatory level. (2) Vasogenic brain edema due to compromised blood-brain barrier, transformation of the endothelial cell surface from an anticoagulant to a procoagulant surface are important factors in the pathogenesis of ischemic stroke. (3) Release of prostaglandins, endothelin-1, complement proteins, and matrix metalloproteinase-9 by microvascular endothelial cells are other components in the complex mechanism of brain ischemia/hypoxia. (4) Ultrastructural studies documented the opened paracellular avenues in the course of vasogenic edema in different experimental models (5) Tight junctions of endothelial cells have been characterized with freeze fracture electron microscopy, and the process of transvesiculation was analyzed using rapid freeze and freeze substitution procedure before electron microscopy studies (6) In endothelial cell-culture experiments, we used rodent and later human brains. (7) Endothelial cells co-cultured with astroglia resulted in an elaborate tight junctional complex. (8) This co-culture technique becomes the basis of in vitro blood-brain barrier studies On endothelial cells of human brain origin, different regulatory factors found to be responsible for the complex mechanism of ischemic stroke.
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PMID:Human cerebral microvessel endothelial cell culture as a model system to study the blood-brain interface in ischemic/hypoxic conditions. 1596 14

Laparoscopic techniques are increasingly applied for the treatment of diverse gastrointestinal diseases. With regard to reports of a pronounced decrease of intra-abdominal blood flow with increasing intra-abdominal pressure, the present study investigates the impact of pressure and gas type on ischemia in small bowel anastomoses in the rat model. Laparotomy and ileoileal anastomosis were performed in 39 male Sprague-Dawley rats. A CO2 or helium pneumoperitoneum of 3 mm Hg or of 6 mm Hg was maintained before and after anastomoses. Rats in the control group received no pneumoperitoneum. Animals were sacrificed after 5 d, and the anastomotic region was explanted for subsequent histopathological examinations. In hematoxylin and eosin (HE)-stained sections, the Chiu score, villi configuration, and number of goblet cells were analyzed. Proliferation (Ki67) and expression of a matrix metalloproteinase (MMP-8) were examined by immunohistochemistry. Mucosal damage according to the scoring system by Chiu, the number of goblet cells, the villus length, the proliferation (Ki67), and the submucosal expression of MMP-8 was similar in all groups. Our results suggest that within a certain range of pressures and time, laparoscopic assisted surgery using CO2 pneumoperitoneum can be performed safely. Helium gas offers no advantages over CO2.
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PMID:Influence of pneumoperitoneum on small bowel anastomoses: a histological analysis in the rat model. 1603 74

Ischemia is a leading cause of acute renal failure (ARF), a disease associated with high morbidity and mortality. Disruption of intercellular adhesion in the proximal tubules is linked to ARF, although the molecular mechanism(s) remains unclear. Our previous studies showed that ischemia is associated with cadherin cleavage and loss in NRK cells, putatively due to a matrix metalloproteinase (MMP) (7). In the current studies, a MMP required for E-cadherin cleavage and N-cadherin loss was identified. Chemical inhibitors against a number of soluble MMPs (1, 2, 3, 8, 9) failed to completely attenuate ischemia-induced cadherin loss. Under ischemic conditions, there was an increase in active membrane-type (MT)1-MMP but a decrease in MMP-2 protein expression. Plating cells on fibronectin protected against ischemia-induced loss of cadherins and, interestingly, no increase in active MT1-MMP levels was seen in ischemic cells on fibronectin-coated dishes. In addition, L cells stably expressing E- (LE) or N-cadherin (LN), but lacking MT1-MMP expression, were resistant to ischemia-induced cadherin loss. The role of MT1-MMP in ischemia-induced cadherin loss was confirmed by either blocking MT1-MMP activity with a neutralizing antibody or expression with shRNA constructs which protected full-length E- and N-cadherin during ischemia. Using shRNA constructs to suppress MT1-MMP expression, ischemia-induced disruption of cadherin function was ablated, and cell-cell contacts were preserved. These results demonstrate that ischemia induces increased expression of active MT1-MMP and subsequent disruption of cadherin/catenin complexes, implying that MT1-MMP plays a role in ischemia-induced ARF.
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PMID:Ischemia-induced cleavage of cadherins in NRK cells requires MT1-MMP (MMP-14). 1607 81

Mast cells accumulate in tissues undergoing angiogenesis during tumor growth, wound healing, and tissue repair. Mast cells can secrete angiogenic factors such as vascular endothelial growth factor (VEGF). Ionizing irradiation has also been shown to have angiogenic potential in malignant and nonmalignant diseases. We observed that low-dose irradiation fosters mast cell-dependent vascular regeneration in a limb ischemia model. Irradiation promoted VEGF production by mast cells in a matrix metalloproteinase-9 (MMP-9)-dependent manner. Irradiation, through MMP-9 up-regulated by VEGF in stromal and endothelial cells, induced the release of Kit-ligand (KitL). Irradiation-induced VEGF promoted migration of mast cells from the bone marrow to the ischemic site. Irradiation-mediated release of KitL and VEGF was impaired in MMP-9-deficient mice, resulting in a reduced number of tissue mast cells and delayed vessel formation in the ischemic limb. Irradiation-induced vasculogenesis was abrogated in mice deficient in mast cells (steel mutant, Sl/Sl(d) mice) and in mice in which the VEGF pathway was blocked. Irradiation did not induce progenitor mobilization in Sl/Sl(d) mice. We conclude that increased recruitment and activation of mast cells following irradiation alters the ischemic microenvironment and promotes vascular regeneration in an ischemia model. These data show a novel mechanism of neovascularization and suggest that low-dose irradiation may be used for therapeutic angiogenesis to augment vasculogenesis in ischemic tissues.
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PMID:Low-dose irradiation promotes tissue revascularization through VEGF release from mast cells and MMP-9-mediated progenitor cell mobilization. 1615 86

Hyperlipidemia attenuates the cardioprotective effect of preconditioning via unknown mechanisms. We have reported previously that in normolipidemic rats, preconditioning decreased ischemia-induced activation and release of myocardial matrix metalloproteinase (MMP)-2 into the coronary perfusate. Here, we investigated whether hyperlipidemia interferes with the cardioprotective effect of preconditioning through modulation of MMP-2. Hearts isolated from male Wistar rats fed 2% cholesterol-enriched or control chow for 9 weeks were subjected to a preconditioning protocol (three intermittent periods of ischemia/reperfusion of 5-min duration each) or a time-matched nonpreconditioning protocol. This was followed by a test ischemia/reperfusion (30-min ischemia and 120-min reperfusion) in both groups. Preconditioning decreased infarct size in the control but not the cholesterol-fed group. Cardioprotection in the preconditioned control group but not in the cholesterol-fed group was associated with an 18 +/- 3% (p < 0.05) inhibition of test ischemia/reperfusion-induced activation and release of myocardial MMP-2 into the perfusate. Myocardial protein levels of tissue inhibitors of MMPs [tissue inhibitor of metalloproteinases (TIMP)-2 and TIMP-4] were not changed in either group. A reduction of infarct size in nonpreconditioned hearts from both control and cholesterol-fed group was produced by the MMP inhibitor ilomastat at 0.25 microM, a concentration producing MMP-2 inhibition comparable with that of preconditioning in the control group. We conclude that hyperlipidemia blocks preconditioning-induced cardioprotection, hyperlipidemia abolishes preconditioning-induced inhibition of myocardial MMP-2 activation and release, preconditioning-induced inhibition of MMP-2 activation and release is not mediated by TIMPs, and pharmacological inhibition of MMPs produces cardioprotection in both normal and hyperlipidemic rats.
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PMID:Hyperlipidemia attenuates the infarct size-limiting effect of ischemic preconditioning: role of matrix metalloproteinase-2 inhibition. 1616 72

The involvement of matrix metalloproteinases (MMPs) in cerebral ischemia-induced apoptosis was investigated in a model of transient focal cerebral ischemia in rats treated intracerebroventricularly (i.c.v.) with 4-((3-(4-phenoxylphenoxy)propylsulfonyl)methyl)-tetrahydropyran-4-carboxylic acid N-hydroxy amide, a broad spectrum non-peptidic hydroxamic acid MMP inhibitor, and in MMP-9-deficient mice. Our results showed that MMP inhibition reduced DNA fragmentation by 51% (P < 0.001) and cerebral infarct by 60% (P < 0.05) after ischemia. This protection was concomitant with a 29% reduction of cytochrome c release into the cytosol (P < 0.005) and a 54% reduction of calpain-related alpha-spectrin degradation (P < 0.05), as well as with an 84% increase in the immunoreactive signal of the native form of poly(ADP) ribose polymerase (P < 0.01). By contrast, specific targeting of the mmp9 gene in mice did reduce cerebral damage by 34% (P < 0.05) but did not modify the apoptotic response after cerebral ischemia. However, i.c.v. injection of MMP-9-deficient mice with the same broad-spectrum inhibitor used in rats significantly reduced DNA degradation by 32% (P < 0.05) and contributed even further to the protection of the ischemic brain. Together, our pharmacological and genetic results indicate that MMPs other than MMP-9 are actively involved in cerebral ischemia-induced apoptosis.
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PMID:Role of matrix metalloproteinases in apoptosis after transient focal cerebral ischemia in rats and mice. 1619


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