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)

Approaches to regulating angiogenesis in the brain, which may diminish parenchymal damage after stroke, are lacking. Survivin, the inhibitor of apoptosis protein, is up-regulated in vitro in vascular endothelial cells by angiogenic factors, including vascular endothelial cell growth factor (VEGF). To evaluate the in vivo role of survivin in the brain in response to hypoxia/ischemia, we used a mouse model of stroke and show that 2 days after permanent middle cerebral artery occlusion, survivin is uniquely expressed by microvessels that form in the peri-infarct and infarct regions. The extent of vascularization of the infarct is dependent on expression of survivin, since vessel density is significantly reduced in mice with heterozygous deficiency of the survivin gene (survivin+/- mice), even though infarct sizes were not different. Hypoxia alone induces survivin expression in the brain, by cultured endothelial cells and by embryonic stem cells, but this response is at least partially independent of VEGF, hypoxia inducible factor 1alpha, or placental growth factor. Delineating the spatiotemporal pattern of expression of survivin after stroke, and the molecular mechanisms by which this is regulated, may provide novel approaches to therapeutically optimize angiogenesis in a variety of ischemic disorders.
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PMID:Survivin-dependent angiogenesis in ischemic brain: molecular mechanisms of hypoxia-induced up-regulation. 1293 34

Therapeutic angiogenesis has emerged as a promising therapy, but some patients are refractory to exogenous growth factors. In order to identify the genetic determinants of post-natal angiogenesis and physiological vessel formation, we investigated the genetic factors that affected ischemia-induced development of collaterals in mice. An ischemic hindlimb model was generated in C57BL/6, C3H/He, and BALB/c mice. Angiogenesis was markedly different among the mice as determined by the restoration of blood perfusion and capillary density of the ischemic muscle. Impaired collateral vessel formation in BALB/c mice was associated with reduced expression of vascular endothelial cell growth factor (VEGF). Intramuscular gene transfer of VEGF promoted collateral formation in C57BL/6J mice, but not in BALB/c mice. Ineffectiveness of VEGF in BALB/c mice was associated with impaired expression of VEGF receptor. Our findings suggest that genetic background may influence spontaneous collateral formation and therapeutic effectiveness of exogenous VEGF. Alternative strategies other than administration of VEGF alone might be needed to attain optimal angiogenesis in some patients.
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PMID:Genetic background influences therapeutic effectiveness of VEGF. 1451 61

Ischemic injury to the kidney results in blood vessel loss and predisposition to chronic renal disease. Angiostatin is a proteolytic cleavage product of plasminogen that inhibits angiogenesis, promotes apoptosis of endothelial cells, and disrupts capillary integrity. A combination of lysine-Sepharose enrichment followed by Western blotting was used to study the expression of angiostatin in response to the induction of ischemic renal injury. No angiostatin products were readily detectable in kidneys of sham-operated control rats. In contrast, both 38- and 50-kDa forms of angiostatin were dramatically enhanced in the first 3 days following 45-min ischemia-reperfusion injury. Renal angiostatin levels declined but remained detectable at late time points postrecovery (8-35 days postischemia). Angiostatin-like immunoreactivity was also elevated in the plasma and in urine for up to 35 days following injury. Lysine-Sepharose extracts of either kidney or urine inhibited vascular endothelial cell growth factor-induced proliferation of human aortic endothelial cells in vitro; an effect that was blocked by coincubation with an angiostatin antibody. RT-PCR verified that mRNA of the parent protein plasminogen was produced in the liver, but it was not present in either sham-operated or postischemic kidney. Matrix metalloproteinase (MMP)-2 and MMP-9, which may mediate angiostatin generation, were enhanced in postischemic kidney tissue and were localized to the renal tubules, interstitial cells, and the tubulo-interstitial space. These data indicate the possible local synthesis of angiostatin following acute renal failure (ARF) and suggest a possible role for MMPs in this activity. Renal angiostatin generation following ARF may modulate renal capillary density postischemia and thereby influence chronic renal function.
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PMID:Angiostatin and matrix metalloprotease expression following ischemic acute renal failure. 1507 85

The danger model of immunity and tolerance holds that antigen-presenting cells (APCs), activated by stress, injury, or necrosis, but not by physiological (apoptotic) cell death, initiate adaptive immune responses. APC activation is fundamentally associated with binding of CD40 to its ligand CD154. Platelets express CD154 upon activation and are thus potential primal danger signals linking the homeostatic response to trauma to activation of the acquired immune system. Previously, we showed that platelets can undergo gradient-driven migration, or chemotaxis, toward supernatants from cells injured by repeated freeze/thaws, UV light, or ischemia/reperfusion. Herein, we demonstrate that platelet-derived CD154 induces immature dendritic cell maturation with upregulation of costimulatory molecules and IL-12p40 production. Overall, these results provide a mechanism for platelet activation of APC facilitating the induction of adaptive immunity in environments of cell injury.
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PMID:Platelets deliver costimulatory signals to antigen-presenting cells: a potential bridge between injury and immune activation. 1510 73

Calcium dobesilate stabilizes blood-retinal barrier in patients with diabetic retinopathy and possesses antioxidant properties in the retinas of rats with streptozotocin-induced diabetes, exposed ex vivo to ischemia-reperfusion. Here we investigated the action of calcium dobesilate on retinal albumin leakage in streptozotocin-diabetic rats, together with relevant in vivo retinal antioxidant and permeability markers, i.e., carboxymethyl-lysine-advanced glycation end product (CML-AGE) formation and vascular endothelial cell growth factor (VEGF) overexpression. Twenty days after streptozotocin administration, diabetic rats were treated for 10 days with calcium dobesilate (100 mg/kg/day per os) or vehicle. Retinal albumin leakage, CML-AGE formation, and VEGF overexpression were evaluated by immunohistochemistry of frozen eye sections. Diabetic rats exhibited dramatic increases in: (i) retinal albumin leakage (31% of positive vessels vs. 0.2% in nondiabetic rats, P<0.008), (ii) CML-AGE retinal occurrence (40+/-3% vs. undetectable positive vessels), and (iii) retinal VEGF protein expression (14.6+/-1.1 vs. 3.5+/-0.5 VEGF-positive spots/field, P<10(-4)). Calcium dobesilate significantly reduced: (i) retinal albumin leakage (by 70%, P<0.008), (ii) retinal CML-AGEs contents (by 62%, P<0.008), and (iii) retinal VEGF expression (by 69.4%, P<0.008). In conclusion, calcium dobesilate orally given to diabetic rats markedly reduced retinal hyperpermeability, CML-AGE contents, and VEGF overexpression. These results strongly suggest that calcium dobesilate stabilizes blood-retinal barrier in diabetic retinopathy via an in situ antioxidant action. Further studies in patients are required to confirm such view.
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PMID:Reduction of retinal albumin leakage by the antioxidant calcium dobesilate in streptozotocin-diabetic rats. 1524 73

Oxidative stress defined as outbalanced generation of reactive oxygen species (ROS) than the existing antioxidative defense mechanisms plays an important role in tissue injury. Ischemia/reperfusion accompanied during organ transplantation is well- established oxidative stress-induced tissue injury. We hypothesized that oxidative stress may also play a role in the development and progression of chronic allograft nephropathy (CAN), since that ROS are major signaling molecules of growth factors and cytokines [platelet-derived growth factors, transforming growth factor-beta1(TGF-beta1)] upregulated in the kidney of CAN, that ROS in turn upregulate TGF-beta1, and that mycophenolic acid may inhibit features of CAN [proliferation and extracellular matrix (ECM) accumulation in vascular smooth muscle cells and glomerular mesangial cells] through inhibiting cellular ROS. Cellular ROS activate signal transduction cascade (protein kinase C, mitogen-activated protein kinases, and janus kinases) and transcription factors (nuclear factor-kappaB, activated protein-1, specificity protein 1, and signal transducers and activators of transcription) leading to regulation of genes and proteins involved in cellular proliferation, ECM remodeling, and apoptosis accompanied in CAN. This review is intended to provide an overview of oxidative stress in renal allograft nephropathy.
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PMID:Oxidative stress and chronic allograft nephropathy. 1562 96

Delayed cerebral ischemia as a result of cerebral vasospasm is the most common cause of death and disability after aneurysmal subarachnoid hemorrhage (SAH). It leads to death or permanent neurologic deficits in over 17-40% of SAH patients. The initial and main symptom of cerebral vasospasm is diffuse headache and may be accompanied with a slight increase in discomfort from neck stiffness and fever. The clinical diagnosis of cerebral vasospasm is made when the patient experiences an altered level of consciousness or a new focal neurologic deficit. There has been a great progress in identifying the patients at risk, putative mechanisms, and possible treatment options for cerebral vasospasm. However, the problem is by no means solved, mainly due to a limited understanding of the pathologic mechanisms of this complex disease. The iatrogenic factors that can increase the risk of cerebral vasospasm include prolongation of the subarachnoid clot by antifibrinolytic drugs, hypotension, inappropriate treatment of hyponatremia, hypovolemia, hyperthermia and increased intracranial pressure. Nimodipine has been shown to improve neurologic outcome and decrease the incidence of cerebral vasospasm. Triple H therapy is a treatment designed to augment cerebral blood flow for patient with cerebral vasospasm. Hypervolemic hypertension is induced with intravenous volume expansion with crystalloid or colloid to increase cardiac output and raise blood pressure. However, small randomized trials showed no clear benefit. Recently, balloon and chemical angioplasty with superselective intra-arterial injection of vasodilators has emerged as the primary intervention for treating medically refractory ischemia from cerebral vasospasm and in many centers is being used as a first-line treatment or even prophylactically. In addition, promising new treatments for cerebral vasospasm or its ischemic complications include magnesium sulfate, fasudil hydrochloride, tirilazad mesylate, erythropoietin, and induced hypothermia; however, all still need further clinical trials. Newly recognized mediators of cerebral vasospasm after SAH include endothelium-derived mediators, vascular smooth-muscle-derived mediators, proinflammatory mediators involved in blood-brain barrier disruption, cytokines and adhesion molecules, stress-induced gene activation, and platelet-derived growth factors. Moreover, observations in the laboratory have, in many circumstances, matched those of reported small series. Larger, prospective, randomized trials are needed to verify several hypotheses of molecular pathophysiology and clinical treatment regimens.
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PMID:Treatment of cerebral vasospasm after subarachnoid hemorrhage--a review. 1567 31

The development of new blood vessels is a complex process, likely requiring the synergy of multiple angiogenic mediators. This study focuses on the proximal angiogenic response using the platelet as a complex carrier of critical mediators of angiogenesis. Platelet levels are controlled by circulating levels of thrombopoietin (TPO) functioning to activate megakaryocyte differentiation and platelet release through the c-mpl receptor. We hypothesized that TPO gene transfer should enhance correction of experimental ischemia by providing increased levels of platelets and hence platelet-derived mediators of angiogenesis. To evaluate this hypothesis, we dissected the role of the TPO-c-mpl-megakaryocyte-platelet pathway in the angiogenic response using a model of acute hindlimb ischemia of wild-type, TPO(-/-), and c-mpl(-/-) mice. The data demonstrate that infusion of platelets will enhance the angiogenic response in wild-type mice and that the endogenous angiogenic response is blunted in TPO(-/-) and c-mpl(-/-) mice. Consistent with this observation, adenovirus (Ad)-mediated transfer of TPO (AdTPO) enhanced the correction of ischemia in wild-type and TPO(-/-), but not c-mpl(-/-), mice. Local versus systemic administration of AdTPO showed that the effect of TPO gene transfer was systemic, not local, and it could be replaced by gene transfer of VEGF, one of the many mediators of angiogenesis carried by the platelets, even in the absence of components in the TPO-c-mpl-megakaryocyte-platelet pathway.
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PMID:Thrombopoietin gene transfer-mediated enhancement of angiogenic responses to acute ischemia. 1605 88

Platelets become activated during myocardial infarction (MI), but the direct contribution of activated platelets to myocardial reperfusion injury in vivo has yet to be reported. We tested the hypothesis that activated platelets contribute importantly to reperfusion injury during MI in mice. After 30 min of ischemia and 60 min of reperfusion, P-selectin knockout mice had a significantly smaller infarct size than that of wild-type mice (P < 0.05). Platelets were detected by P-selectin antibody in the previously ischemic region of wild-type mice as early as 2 min postreperfusion after 45 min, but not 20 min, of ischemia. The appearance of neutrophils in the heart was delayed when compared with platelets. Flow cytometry showed that the number of activated platelets more than doubled after 45 min of ischemia when compared with 20 min of ischemia or sham treatment (P < 0.05). Platelet-rich or platelet-poor plasma was then transfused from either sham-operated or infarcted mice after 45 and 10 min of ischemia-reperfusion to mice undergoing 20 and 60 min of ischemia-reperfusion. Infarct size was increased by threefold and platelet accumulation was remarkably enhanced in mice treated with wild-type, MI-activated platelet-rich plasma but not in mice receiving either platelet-poor plasma from wild types or MI-activated platelet-rich plasma from P-selectin knockout mice. In conclusion, circulating platelets become activated early during reperfusion and their activation depends on the duration of the preceding coronary occlusion and is proportional to the extent of myocardial injury. Activated platelets play an important role in the process of myocardial ischemia-reperfusion injury, and platelet-derived P-selectin is a critical mediator.
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PMID:Activated platelets contribute importantly to myocardial reperfusion injury. 1619 80

The association between malignancy and venous thrombotic events is well established. However, arterial thrombosis among cancer patients is extremely rarely reported. There are several mechanisms of arterial thrombosis or embolism in malignancy. Important mechanisms in arterial thrombogenesis are shear stress-induced platelet aggregation and platelet-derived microparticles. Both of these are induced by major abdominal surgery. A major abdominopelvic surgery followed by adjuvant platinum-based combined chemotherapy is routinely performed for epithelial ovarian cancer which is the leading cause of death among all gynecologic malignancies. These patients have a greater risk of arterial thrombosis at the postoperative period. If the affected arteries are relatively larger, clinical findings will be evident due to limb ischemia or fatal organ infarctions. However, thrombosis of the small arteries disturbs the tissue circulation which is extremely important for the chemotherapeutic agents to reach the residual tumor cells. When the thrombosis of small arteries is prevented, these drugs will reach all of the residual macroscopic or microscopic tumoral tissues and so the prognosis of the patients may be improved. Therefore, we hypothesize that anti-platelet therapy with aspirin is needed to be initiated during the postoperative period of epithelial ovarian cancer patients and be continued as long as chemotherapy goes on. Such an approach might have a role in optimizing the oncological prognosis of these patients via increasing the effectiveness of cytotoxic therapy since some of the recurrences may be caused by some microscopic tumor foci which were not affected by cytotoxic drugs because of subclinical small arterial thromboses.
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PMID:Use of anti-thrombotic agents during chemotherapy for epithelial ovarian cancer. 1644 52


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