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

Extracellular matrix (ECM) metabolism and homeostasis is sensitive to changes in oxygen tension manifest in ischemia. We hypothesize that in chronically ischemic limbs, abnormalities in uninjured skin, secondary to hypoxia, predispose to dermal breakdown. Paired biopsies of uninjured distal ischemic and proximal non-ischemic skin were harvested at below knee amputation from 14 patients with peripheral vascular disease following quantification of ischemia. Age- and site-matched controls were taken at total knee replacement (TKR) and varicose vein (VV) operations. Matrix metalloproteinase (MMP)-2 and -9 expression was determined using gelatin zymography, MMP-1 by western blotting and ELISA and tissue inhibitor of MMP (TIMP) by reverse zymography. Collagen content was measured by determining hydroxyproline levels, and collagen type I synthesis by ELISA. Collagen type I synthesis was upregulated in ischemic tissue compared with non-ischemic matched pairs (p<0.001) and both TKR and VV controls, however, there was no increase in collagen deposition. Levels of MMP-2 (p<0.0005) and TIMP-2 (p<0.01), were elevated in ischemic samples. MMP-9 was unaltered, signifying no inflammatory changes. Tissue ischemia was linked to elevated ECM turnover, associated with matrix failure when compounded with problems of matrix stabilization, likely in ischemia. This represents a potential mechanism for ulcer formation.
 ...
PMID:Abnormal extracellular matrix metabolism in chronically ischemic skin: a mechanism for dermal failure in leg ulcers. 1609 24

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.
 ...
PMID:Ischemia injury alters endothelial cell properties of kidney cortex: stimulation of MMP-9. 1611 9

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.
 ...
PMID:Hyperlipidemia attenuates the infarct size-limiting effect of ischemic preconditioning: role of matrix metalloproteinase-2 inhibition. 1616 72

Sepsis causes more than with 215,000 deaths per year in the United States alone. Death can be caused by multiple system organ failure, with the lung, in the form of the acute respiratory distress syndrome (ARDS), often being the first organ to fail. We developed a chronic porcine model of septic shock and ARDS and hypothesized that blocking the proteases neutrophil elastase (NE) and matrix metalloproteinases (MMP-2 and MMP-9) with the modified tetracycline, COL-3, would significantly improve morbidity in this model. Pigs were anesthetized and instrumented for hemodynamic monitoring and were then randomized to one of three groups: control (n = 3), laparotomy only; superior mesenteric artery occlusion (SMA) + fecal blood clot (FC; n = 7), with intraperitoneal placement of a FC; and SMA + FC + COL (n = 5), ingestion of COL-3 12 h before injury. Animals emerged from anesthesia and were monitored and treated with fluids and antibiotics in an animal intensive care unit continuously for 48 h. Serum and bronchoalveolar lavage fluid (BALF) were sampled and bacterial cultures, MMP-2, MMP-9, NE, and multiple cytokine concentrations were measured. Pigs were reanesthetized and placed on a ventilator when significant lung impairment occurred (PaO2/FiO2 < 250). At necropsy, lung water and histology were assessed. All animals in the SMA + FC group developed septic shock evidenced by a significant fall in arterial blood pressure that was not responsive to fluids. Lung injury typical of ARDS (i.e., a fall in lung compliance and PaO2/FiO2 ratio and a significant increase in lung water) developed in this group. Additionally, there was a significant increase in plasma IL-1 and IL-6 and in BALF IL-6, IL-8, IL-10, NE, and protein concentration in the SMA + FC group. COL-3 treatment prevented septic shock and ARDS and significantly decreased cytokine levels in plasma and BALF. COL-3 treatment also significantly reduced NE activity (P < 0.05) and reduced MMP-2 and MMP-9 activity in BALF by 64% and 34%, respectively, compared with the SMA + FC group. We conclude that prophylactic COL-3 prevented the development of ARDS and unexpectedly also prevented septic shock in a chronic insidious onset animal model of sepsis-induced ARDS. The mechanism of this protection is unclear, as COL-3 inhibited numerous inflammatory mediators. Nevertheless, COL-3 significantly reduced the morbidity in a clinically applicable animal model, demonstrating the possibility that COL-3 may be useful in reducing the morbidity associated with sepsis and ischemia/reperfusion injury in patients.
 ...
PMID:Chemically modified tetracycline prevents the development of septic shock and acute respiratory distress syndrome in a clinically applicable porcine model. 1620 20

Chronic limb-threatening ischemia is a devastating disease with limited surgical options. However, inducing controlled angiogenesis and enhancing reperfusion holds therapeutic promise. To gain a better understanding of the mechanisms that contribute to limb reperfusion, we examined the temporal biochemical and structural changes occurring within the extracellular matrix of ischemic skeletal muscle. Both the latent and active forms of MMP-2 and -9 significantly increased during the active phase of limb reperfusion. Moreover, small but significant alterations in tissue inhibitors of metalloproteinase levels also occurred during a similar time course, consistent with a net increase in extracellular matrix remodeling. This temporal increase in MMP activity coincided with enhanced exposure of the unique HU177 cryptic collagen epitope. Although the HUIV26 cryptic collagen epitope has been implicated in angiogenesis, little is known concerning such epitopes within ischemic muscle tissue. Here, we provide the first evidence that a functionally distinct cryptic collagen epitope (HU177) is temporally exposed in ischemic muscle tissue during the active phase of reperfusion. Interestingly, the exposure of the HU177 epitope was greatly diminished in MMP-9 null mice, corresponding with significantly reduced limb reperfusion. Therefore, the regulated exposure of a unique cryptic collagen epitope within ischemic muscle suggests an important role for collagen remodeling during the active phase of ischemic limb reperfusion.
 ...
PMID:Temporal exposure of cryptic collagen epitopes within ischemic muscle during hindlimb reperfusion. 1625 19

We reported previously that predelivery of the anti-oxidant gene heme oxygenase-1 (HO-1) to the heart by adeno associated virus (AAV) markedly reduces injury after acute myocardial infarction (MI). However, the effect of HO-1 gene delivery on postinfarction recovery has not been investigated. In the current study, we assessed the effect of HO-1 gene delivery on post-MI left ventricle (LV) remodeling and function using echocardiographic imaging and histomorphometric approaches. Two groups of Sprague-Dawley rats were injected with 4 x 10(11) particles of AAV-LacZ (control) or AAV-hHO-1 in the LV wall. Eight wk after gene transfer, the animals were subjected to 30 min of ischemia by ligation of left anterior descending artery (LAD) followed by reperfusion. Echocardiographic measurements were obtained in a blinded fashion prior and at 1.5 and 3 months after I/R. Ejection fraction (EF) was reduced by 13% and 40% in the HO-1 and LacZ groups, respectively at 1.5 months after MI. Three months after MI, EF recovered fully in the HO-1, but only partially in the LacZ-treated animals. Post-MI LV dimensions were markedly increased and the anterior wall was markedly thinned in the LacZ-treated animals compared with the HO-1-treated animals. Significant myocardial scarring and fibrosis were observed in the LacZ-group in association with elevated levels of interstitial collagen I and III and MMP-2 activity. Post-MI myofibroblast accumulation was reduced in the HO-1-treated animals, and retroviral overexpression of HO-1 reduced proliferation of isolated cardiac fibroblasts. Our data indicate that rAAV-HO-1 gene transfer markedly reduces fibrosis and ventricular remodeling and restores LV function and chamber dimensions after myocardial infarction.
 ...
PMID:Heme oxygenase-1 (HO-1) inhibits postmyocardial infarct remodeling and restores ventricular function. 1644 92

Matrix metalloproteinases-2 and -9 (MMP-2/9) are critically involved in degradation of extracellular matrix, and their inhibition is discussed as a promising strategy against hepatic ischemia-reperfusion (I/R) injury. Here, we analyzed the role of MMP-2 and -9 for leukocyte migration and tissue injury in sham-operated mice and in mice after I/R, treated with a MMP-2/9 inhibitor or vehicle. Using zymography, we show that the MMP-2/9 inhibitor abolished I/R-induced MMP-9 activation, whereas MMP-2 activity was not detectable in all groups. As demonstrated by intravital microscopy, MMP-9 inhibition attenuated postischemic rolling and adherence of total leukocytes in hepatic postsinusoidal venules, CD4+ T cell accumulation in sinusoids, and neutrophil transmigration. These effects were associated with reduction of plasma tumor necrosis factor alpha (TNF-alpha) levels and endothelial expression of CD62P. Motility of interstitially migrating leukocytes was assessed by near-infrared reflected light oblique transillumination microscopy in the postischemic cremaster muscle. Upon MMP-9 blockade, leukocyte migration velocity and curve-line and straight-line migration distances were reduced significantly as compared with the vehicle-treated I/R group. Postischemic sinusoidal perfusion failure, hepatocellular apoptosis, and alanine aminotransferase activity were only slightly reduced after MMP-9 inhibition, whereas aspartate aminotransferase activity and mortality were significantly lower. In conclusion, MMP-9 is involved in the early recruitment cascades of neutrophils and CD4+ T cells, promotes neutrophil and T cell transmigration during hepatic I/R, and is required for motility of interstitially migrating leukocytes. MMP-9 blockade is associated with an attenuation of TNF-alpha release and endothelial CD62P expression, weakly protects from early microvascular/hepatocellular I/R damage, but improves postischemic survival.
 ...
PMID:Matrix metalloproteinase-9 promotes neutrophil and T cell recruitment and migration in the postischemic liver. 1655 80

Thrombolysis with tissue plasminogen activator (tPA) is the only pharmacotherapy available for cerebral ischemia. However, the use of tPA can increase the risk of hemorrhage due to blood-brain barrier (BBB) breakdown. Recent evidence suggests that increased activation of matrix metalloproteinases (MMPs) may be involved in this breakdown. This study examines the temporal profile of MMP-2 and -9 following tPA administration to ischemic rats. Male Sprague-Dawley rats were randomly assigned to one of four groups (Sham-tPA; Sham-Saline; Ischemia-tPA; Ischemia-Saline; group n = 6, total N = 120). Focal embolic ischemia was induced by middle cerebral artery occlusion through injection of an autologous clot. One hour post-surgery, tPA (10 mg/kg) or saline was delivered intravenously and animals were euthanized at 3, 6, 12, or 24 h after onset of ischemia. Infarct volume was measured by TTC staining; BBB components examined immunohistochemically; and MMP activation measured by gelatin zymography. Our results show that tPA significantly reduced infarct volumes (overall infarct volume-Sham-tPA: 5.80 +/- 4.55 [mean +/- SE]; Sham-Saline: 5.00 +/- 4.23; Ischemia-tPA: 186.1 +/- 73.45; Ischemia-Saline: 284.8 +/- 88.74; all P < 0.05). Treatment with tPA was also associated with the activation of MMP-9 at 6, 12, and 24 h following ischemia. No temporal changes were observed in MMP-2 activation, although tPA administration increased its activity compared to saline treatment. Analyses of immunohistochemistry showed that destruction of components of the BBB followed MMP-9 activation. Thus, increased MMP-9 activation may, in part, be responsible for the increases in hemorrhagic transformation reported with use of tPA. Our study is the first to demonstrate the temporal profile of MMP activation following thrombolysis with tPA in a model of thrombotic focal cerebral ischemia.
 ...
PMID:Matrix metalloproteinase activation and blood-brain barrier breakdown following thrombolysis. 1662 94

Intrauterine growth restriction (IUGR) increases the risk of developing adult-onset cardiovascular disease. We hypothesized that IUGR resulting from maternal hypoxia or nutrient restriction during late gestation will produce cardiac remodeling and impair cardiac recovery after ischemia/reperfusion (I/R) in adult male offspring aged 4 or 7 mo. Sprague-Dawley rats were randomized on day 15 of pregnancy to hypoxia (IUGR-H, 12% oxygen), nutrient restriction (IUGR-NR, 40% of control diet) or control (room air) groups. In 4-mo IUGR-H offspring, left ventricular wt/body wt ratio (LVW/BW) and right ventricular wt/BW ratio (RVW/BW) increased, in association with increased collagen I and III expression, beta and alpha myosin heavy chain (beta/alphaMHC) ratio, and decreased matrix metalloproteinase (MMP)-2 activity compared to the other groups. Left ventricular end diastolic pressure was higher in perfused hearts. Functional recovery after I/R was remarkably reduced (10+/-3%) compared to both control (39+/-5%) and IUGR-NR rats (32+/-4%). At 7 mo, both IUGR-H and IUGR-NR offspring had increased LVW/BW, collagen I and III, beta/alpha MHC ratio, and decreased cardiac recovery and MMP-2 activity compared to control. These findings suggest that hypoxia or undernutrition during development leads to pathological cardiac remodeling, diastolic dysfunction, and increased sensitivity to ischemic injury during adult life.
 ...
PMID:Hypoxia or nutrient restriction during pregnancy in rats leads to progressive cardiac remodeling and impairs postischemic recovery in adult male offspring. 1663 94

Chronic intermittent high altitude (IHA) hypoxia results in long-term adaptation protecting the heart against acute ischemia/reperfusion injury; however, molecular mechanisms of this phenomenon are not completely elucidated so far. The present study was aimed at investigation of a modulating effect of IHA hypoxia on the expression and/or activation of selected regulatory proteins, with particular emphasis on differential responses in the right ventricle (RV) and left ventricle (LV). Adult male Wistar rats were exposed to IHA hypoxia of 7000 m simulated in a hypobaric chamber (8 h/day, 25 exposures), and protein contents and activities in myocardial fractions were determined by Western blot analysis. In markedly hypertrophic RV of hypoxic rats, gelatinolytic activity of MMP-2 and protein levels of carbonic anhydrase IX (a marker of hypoxia) were significantly enhanced. Study of mitogen-activated protein kinases (MAPKs) revealed no differences in the contents of total p38-MAPK in both ventricles between the IHA and normoxic control rats, whereas activation of p38-MAPK was decreased in the RV and moderately increased in the LV of IHA rats as compared to controls. Extracellular signal regulated kinase-2 (ERK-2) was partially up-regulated in the RV of IHA rats, and, in addition, expression of acidic fibroblast growth factor (aFGF), a potential activator of ERK cascade, was also significantly increased. In contrast, expression of ERKs in the LV as well as their activities in both ventricles, were not affected by IHA hypoxia. Differential effects of IHA hypoxia on c-Jun-N-terminal protein kinases (JNKs) in the RV and LV were also observed. As compared with the controls, total content of JNKs was increased in the RV of the IHA rats, while expression of JNKs in the LV was down-regulated. IHA hypoxia changed neither total levels of Akt kinase in both RV and LV, nor Akt kinase activity in the RV. However, increased levels of activated phospho-Akt kinase were found in the LV of IHA rats. The results demonstrate that adaptation of rat hearts to chronic IHA hypoxia is associated with disctinct changes in the levels and/or activation of several regulatory proteins in two ventricles. The latter could be attributed to both myocardial remodeling and cardioprotection induced by chronic hypoxia.
 ...
PMID:Changes in the expression and/or activation of regulatory proteins in rat hearts adapted to chronic hypoxia. 1671 73


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>