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)

A major obstacle that limits the potential of human gene therapy is the inefficiency of gene delivery to appropriate sites in vivo. Previous studies demonstrated that the physiological surveillance function performed by von Willebrand factor (vWF) could be incorporated into retroviral vectors by molecular engineering of the MuLV ecotropic envelope (Env) protein. To advance the application of vWF targeting technology beyond laboratory animals, we prepared an extensive series of Env proteins bearing modified vWF-derived matrix-binding sequences and assembled these chimeric proteins into targeted vectors that are capable of transducing human cells. Initially, a dual envelope configuration was utilized, which required coexpression of a wild-type amphotropic Env. Subsequently, streamlined "escort" Env proteins were constructed wherein the inoperative receptor-binding domain of the targeting partner was replaced by the vWF-derived collagen-binding motif. Ultimately, an optimal construct was developed that exhibited properties of both extracellular matrix (ECM)-targeting and near wild-type amphotropic infectivity, and could be arrayed as a single envelope on a retroviral particle. On intraarterial instillation, enhanced focal transduction of neointimal cells (approximately 20%) was demonstrated in a rat model of balloon angioplasty. Moreover, transduction of tumor foci (approximately 1-3%) was detected after portal vein infusion of a matrix-targeted vector in a nude mouse model of liver metastasis. We conclude that the unique properties of these targeted injectable retroviral vectors would be suitable for improving therapeutic gene delivery in numerous clinical applications, including vascular restenosis, laser and other surgical procedures, orthopedic injuries, wound healing, ischemia, arthritis, inflammatory disease, and metastatic cancer.
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PMID:Molecular engineering of matrix-targeted retroviral vectors incorporating a surveillance function inherent in von Willebrand factor. 1081 Dec 27

A case of cerebral angiomatosis in a cat was associated with neurologic signs characterized by clusters of severe generalized seizures. Bilaterally in the gray matter, most prominent in the cingulate gyrus, there was focal accumulation of garlandlike arrangements of blood vessels. Vessels exhibited activated, hypertrophic endothelial cells and thickening and progressive dystrophic mineralization of the basement membrane, with complete luminal obstruction of some affected vessels. Thickening of the basement membrane was due to accumulation of endothelium-derived proteins such as laminin and von Willebrand factor. Furthermore, moderate diffuse astrogliosis was observed. Findings indicate an idiopathic angiomatosis, with clinical signs possibly due to ischemia resulting from narrowing or complete obliteration of vessel lumina. Changes represent a unique endothelial cell-derived lesion within the brain not previously described in humans or domestic animals.
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PMID:Bilateral focal cerebral angiomatosis associated with nervous signs in a cat. 1135 71

To elucidate a role of costimulatory molecule and cell adhesion molecule in hepatic ischemia/reperfusion injury, we examined an alteration in B7-1 (CD80), B7-2 (CD86), and intercellular adhesion molecule 1 (ICAM-1; CD54) expression in the rat liver after warm ischemia/reperfusion injury. To induce hepatic warm ischemia in a rat model, both portal vein and hepatic artery entering the left-lateral and median lobes were occluded by clamping for 30 minutes or 60 minutes, and then reperfused for 24 hours. B7-1, B7-2, and ICAM-1 expressions in the liver were analyzed by immunofluorescence staining and real-time reverse transcription polymerase chain reaction (RT-PCR). Although B7-1 and B7-2 expressions were at very low levels in the liver tissues from normal or sham-operated control rats, both B7-1 and B7-2 expressions were enhanced at protein and messenger RNA (mRNA) levels in the affected, left lobes after warm ischemia/reperfusion. ICAM-1 protein and mRNA were constitutively expressed in the liver of normal and sham-operated control rats, and further up-regulated after warm ischemia/reperfusion. Localization of increased B7-1, B7-2, and ICAM-1 proteins, as well as von Willebrand factor as a marker protein for endothelial cells, was confined by immunofluorescence staining to sinusoidal endothelial cells in hepatic lobules. Data from quantitative real-time RT-PCR analysis revealed that B7-1 and B7-2 mRNA levels were elevated in hepatic lobes after warm ischemia/reperfusion (5.13- and 52.9-fold increase, respectively), whereas ICAM-1 mRNA expression was rather constitutive but further enhanced by warm ischemia/reperfusion (4.24-fold increase). These results suggest that hepatic sinusoidal endothelial cells play a pivotal role as antigen-presenting cells by expressing B7-1 and B7-2 in warm hepatic ischemia/reperfusion injury, and that B7-1 and/or B7-2 might be the primary target to prevent early rejection and inflammatory reactions after hepatic ischemia/reperfusion injury associated with liver transplantation.
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PMID:Enhanced expression of B7-1, B7-2, and intercellular adhesion molecule 1 in sinusoidal endothelial cells by warm ischemia/reperfusion injury in rat liver. 1158 72

We investigated whether circulating endothelial progenitor cells contribute to neovascularization after stroke. Donor bone marrow cells obtained from transgenic mice constitutively expressing beta-galactosidase transcriptionally regulated by an endothelial-specific promoter, Tie2, were injected into adult mice. Focal cerebral ischemia was induced by embolic middle cerebral artery (MCA) occlusion and changes of cerebral blood flow (CBF) were measured by perfusion-weighted magnetic resonance imaging (MRI). Laser scanning confocal microscopy (LSCM), immunohistochemistry and X-gal staining were performed. Perfusion-weighted MRI demonstrated increases in CBF around the boundary of an infarct area 1 month after ischemia. Morphological and 3-dimensional image analyses revealed enlarged and thin-walled blood vessels with sprouting or intussusception at the boundary of the ischemic lesion, which closely corresponded to elevated CBF areas detected on perfusion-weighted MRI, indicating the presence of neovascularization. X-gal and double immunostaining demonstrated that Tie2-lacZ-positive cells incorporated into sites of neovascularization at the border of the infarct, and these cells exhibited an endothelial antigenic marker (von Willebrand factor). In addition, bone marrow recipient mice without ischemia showed incorporation of Tie2-lacZ-expressing cells into vessels of the choroid plexus. These data suggest that formation of new blood vessels in the adult brain after stroke is not restricted to angiogenesis but also involves vasculogenesis and that circulating endothelial progenitor cells from bone marrow contribute to the vascular substructure of the choroid plexus.
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PMID:Bone marrow-derived endothelial progenitor cells participate in cerebral neovascularization after focal cerebral ischemia in the adult mouse. 1186 16

Human diabetic neuropathy is multifactorial in etiology, with ischemia as a final common pathology. Although impaired vascular endothelial cell function in diabetic microvascular injury is established, the role of thrombomodulin (TM)-dependent protein C antithrombotic mechanism in the pathogenesis of neuropathy is unclear. This neuropathologic case-control study investigated whether vascular endothelial TM expression is deficient in peripheral nerve microvessels in diabetic neuropathy. Sural nerve biopsies from 7 patients with diabetic neuropathy and 10 with axonal neuropathy without vasculopathy were immunostained with anti-TM and anti-von Willebrand factor (vWF; an endothelial cell marker) antibodies. The proportion of TM-positive microvessels was expressed relative to total vWF-staining vessels, according to vessel caliber and regional distribution within the nerve. In diabetic nerves compared with reference controls, the proportion of TM-positive endoneurial microvessels was 15-fold lower (0.02 vs. 0.30 in diabetic nerves vs. controls, P < 0.004), and the proportion of small-caliber epineurial microvessels was 10-fold lower (0.04 vs. 0.43, P < 0.001). No TM expression was detected at the perineurium in diabetic or control nerves. We demonstrate a substantial reduction of vascular endothelial TM expression throughout human diabetic neuropathy. These findings suggest that an impaired native TM-dependent protein C antithrombotic mechanism may contribute to microvascular ischemia in the pathogenesis of diabetic neuropathy.
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PMID:Thrombomodulin deficiency in human diabetic nerve microvasculature. 1203 86

Thrombomodulin (TM), a vascular endothelial receptor, terminates the actions of thrombin and accelerates activated protein C formation. TM is ubiquitous throughout the systemic microcirculation but is reduced in brain regions predisposed to lacunar infarction. We investigated whether TM is present within human nerve and differentially expressed according to vessel caliber and proximity to the blood-nerve barrier. Vascular endothelial TM was detected on sural nerve biopsies with immunohistochemistry. The proportion of TM-positive microvessels was expressed relative to total von Willebrand factor (vWF)-positive vessels. Although vWF was detectable in all microvessels, TM expression was absent from the perineurial vessels. TM was detected in 47% (15-80%, 95% confidence level) of larger epineurial arterioles, in 43% (30-61%) of smaller epineurial vessels, and in 30% (19-47%) of endoneurial vessels. These findings demonstrate that TM is present in human nerve microvasculature but is regionally deficient in proximity to the blood-nerve barrier, which may predispose nerve to microvascular ischemia in inflammatory/prothrombotic conditions.
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PMID:Reduced thrombomodulin in human peripheral nerve microvasculature. 1221 Mar 86

Identification of factors that may stimulate ischemia-induced neovascularization without increasing atherosclerotic plaque progression is of major therapeutic importance. We hypothesized that interleukin-18 binding protein (IL-18BP), a major antiinflammatory protein with plaque-stabilizing activities, may affect the neovascularization in mice ischemic hindlimb. Ischemia was produced by artery femoral occlusion in mice that were subjected to in vivo intramuscular electrotransfer of either an empty plasmid or a murine IL-18BP plasmid. Angiographic score, capillary density (CD31 staining), and laser Doppler perfusion data at day 28 showed significant improvement in ischemic/nonischemic leg ratio by respectively 1.6-, 1.4-, and 1.5-fold in IL-18BP-treated mice compared with controls (P<0.01). This was associated with a significant 2-fold increase in both vascular endothelial growth factor (VEGF) and phospho-Akt protein content in the ischemic hindlimb of IL-18BP-treated mice (P<0.05). Similar results were obtained in IL-18-deficient mice. Because bone marrow-derived endothelial progenitor cells (BM-EPCs) are involved in postnatal vasculogenesis, EPCs were isolated and cultivated from bone marrow mononuclear cells. IL-18BP treatment led to a significant 1.8-fold increase in the percentage of BM-EPCs characterized as cells positive for both AcLDL-Dil and von Willebrand factor (P<0.001). In conclusion, IL-18BP stimulates ischemia-induced neovascularization in association with an activation of VEGF/Akt signaling and an increase in BM-EPCs mobilization and differentiation. Our findings strongly suggest a major antiangiogenic role of endogenous IL-18 in postischemic injury.
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PMID:Interleukin-18/interleukin-18 binding protein signaling modulates ischemia-induced neovascularization in mice hindlimb. 1221 94

Thrombotic microangiopathies (TMA) encompass various severe diseases characterized by microangiopathic hemolytic anemia and peripheral thrombocytopenia, associated with fever, neurological signs and renal involvement. Microvascular thrombosis is the typical lesion, and results in tissue ischemia. Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are the two most classical forms. These two entities are clinically and histopathologically closely related. There is a body of evidence suggesting that endothelial cell injury is the initial event in TTP and HUS, and that it may be related to a large number of triggering factors, such as infection, connective tissue disease, drugs, cancer and chemotherapy, transplantation, and pregnancy. Endothelial cell injury enhances the release of ultra large forms of von Willebrand factor (ULvWF) multimers and other prothrombotic agents, such as plasminogen activator inhibitor and platelet activating factor, whereas it decreases the release of prostaglandin-I2, a strong inhibitor of platelet aggregation. Recently however, it has been shown that TTP and HUS were pathophysiologically distinct. Actually, TTP is associated with a deficiency in von Willebrand factor-cleaving protease, an enzyme involved in cleavage of ULvWF into circulating 200 kDa and 350 kDa fragments. This deficiency may be either congenital or acquired, and then related to an IgG inhibitory autoantibody. This protease deficiency may account for the high amounts of plasmatic ULvWF in TTP patients. In HUS, vWF-cleaving protease activity is found normal. HUS encompasses two distinct entities. Epidemic, or diarrhea-associated HUS, is associated with verotoxin or Shiga toxin-associated enterobacteriaceae. These toxins are directly responsible for endothelial cell injury. Sporadic HUS (also termed atypical HUS in children) is closely related to TTP, and shares the same triggering factors. Familial HUS has been associated in some cases with hypocomplementemia and factor H dysfunction, the pathophysiological role of which remains unclear. The study of the different triggering factors and predisposing factors may be useful to define different subsets of TMA, that may be characterized by their course and prognosis.
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PMID:[Pathophysiology of thrombotic microangiopathies: current understanding]. 1221 98

The role of renal microvascular endothelial cell injury in the pathophysiology of ischemic acute renal failure (ARF) remains largely unknown. No consistent morphological alterations have been ascribed to the endothelium of the renal microvasculature as a result of ischemia-reperfusion injury. Therefore, the purpose of this study was to examine biochemical markers of endothelial injury and morphological changes in the renal microvascular endothelium in a rodent model of ischemic ARF. Circulating von Willebrand factor (vWF) was measured as a marker of endothelial injury. Twenty-four hours after ischemia, circulating vWF peaked at 124% over baseline values (P = 0.001). The FVB-TIE2/GFP mouse was utilized to localize morphological changes in the renal microvascular endothelium. Immediately after ischemia, there was a marked increase in F-actin aggregates in the basal and basolateral aspect of renal microvascular endothelial cells in the corticomedullary junction. After 24 h of reperfusion, the pattern of F-actin staining was more similar to that observed under physiological conditions. In addition, alterations in the integrity of the adherens junctions of the renal microvasculature, as demonstrated by loss of localization in vascular endothelial cadherin immunostaining, were observed after 24 h of reperfusion. This observation temporally correlated with the greatest extent of permeability defect in the renal microvasculature as identified using fluorescent dextrans and two-photon intravital imaging. Taken together, these findings indicate that renal vascular endothelial injury occurs in ischemic ARF and may play an important role in the pathophysiology of ischemic ARF.
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PMID:Injury of the renal microvascular endothelium alters barrier function after ischemia. 1268 25

The low-molecular-weight heparins (LMWHs) enoxaparin and dalteparin have shown superior and equivalent efficacy, respectively, over unfractionated heparin (UFH) in patients with unstable angina pectoris (UAP) or non-ST-segment elevation myocardial infarction (NSTEMI). This study aimed to identify markers of blood cell activation that are independent predictors of outcomes at 1 month and to compare the effects of enoxaparin, dalteparin, and UFH on any such markers. In this multicenter, prospective, open-label study, 141 patients with UAP or NSTEMI were randomized to treatment for 48 to 120 hours with enoxaparin (n = 46), dalteparin (n = 48), or UFH (n = 47). Blood samples were taken at the time of randomization and after > or =48 hours of treatment but before catheterization. Multivariate analysis identified increased plasma levels of von Willebrand factor (vWF) and decreased platelet levels of glycoprotein Ib/IX complexes as independent predictors of 1-month adverse outcome (a composite of death, myocardial infarction, and recurrent ischemia). vWF release was strongly related to and may have been released by inflammation as measured by C-reactive protein. Both LMWHs reduced the release of vWF in plasma (as well as C-reactive protein) compared with UFH. Enoxaparin had a more favorable effect on glycoprotein Ib/IX complexes than either dalteparin or UFH. The incidence of the composite clinical efficacy end point was: 13% (enoxaparin), 19% (dalteparin), and 28% (UFH). vWF and its receptor glycoprotein Ib/IX play a key role in acute coronary syndromes. vWF is linked to inflammation and, like glycoprotein Ib/IX, is affected more favorably by the LWMHs than by UFH.
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PMID:Comparison of effects on markers of blood cell activation of enoxaparin, dalteparin, and unfractionated heparin in patients with unstable angina pectoris or non-ST-segment elevation acute myocardial infarction (the ARMADA study). 1268 29


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