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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Edaravone, a newly synthesized synthetic radical scavenger, has been identified and adopted as an anti-stroke agent. However, its mechanism and the effect of edaravone on lipoprotein oxidation are not fully understood. Therefore, whether edaravone could suppress oxidation of low-density lipoprotein (LDL) and be involved in the expression of endothelial nitric oxide synthase (eNOS) in relation to anti-atherogenesis by improving and conserving vascular circulation was investigated. We investigated the in vitro effects of edaravone on copper- and endothelial cell-mediated LDL oxidation, and the expression of eNOS in human umbilical vein endothelial cells (HUVEC) modulated by oxidized LDL. The in vivo effect of edaravone on antioxidative effect was also studied in male rats intravenously administered with edaravone. Edaravone apparently inhibited copper- and HUVEC-mediated LDL oxidation at the concentration equivalent to serum concentrations in clinical use. The intravenous administration of edaravone also enhanced serum radical-scavenging property in rats. We tested the effect of edaravone on protein and mRNA expression of eNOS in HUVEC. Edaravone enhanced eNOS expression in HUVEC, presumably because of increased stability of eNOS mRNA, and reversed eNOS expression reduced by oxidized LDL nearly to the control levels. The present study demonstrates for the first time that edaravone increases eNOS expression with the inhibition of LDL oxidation, and that edaravone can reverse oxidized LDL-mediated reduction in eNOS expression in endothelial cells. The preventive action of edaravone from ischemic disease consequence may be attributed to these eNOS up-regulation with decreased oxidation.
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PMID:Edaravone, a novel radical scavenger, inhibits oxidative modification of low-density lipoprotein (LDL) and reverses oxidized LDL-mediated reduction in the expression of endothelial nitric oxide synthase. 1572 Oct 14

Here, we investigate the effects of endothelial nitric oxide synthase (eNOS) on angiogenesis, neurogenesis, neurotrophic factor expression, and neurological functional outcome after stroke. Wild-type and eNOS knock-out (eNOS-/-) mice were subjected to permanent occlusion of the right middle cerebral artery. eNOS-/- mice exhibited more severe neurological functional deficit after stroke than wild-type mice. Decreased subventricular zone (SVZ) progenitor cell proliferation and migration, measured using bromodeoxyuridine, Ki-67, nestin, and doublecortin immunostaining in the ischemic brain, and decreased angiogenesis, as demonstrated by reduced endothelial cell proliferation, vessel perimeter, and vascular density in the ischemic border, were evident in eNOS-/- mice compared with wild-type mice. eNOS-deficient mice also exhibited a reduced response to vascular endothelial growth factor (VEGF)-induced angiogenesis in a corneal assay. ELISAs showed that eNOS-/- mice have decreased brain-derived neurotrophic factor (BDNF) expression but not VEGF and basic fibroblast growth factor in the ischemic brain compared with wild-type mice. In addition, cultured SVZ neurosphere formation, proliferation, telomerase activity, and neurite outgrowth but not cell viability from eNOS-/- mice were significantly reduced compared with wild-type mice. BDNF treatment of SVZ cells derived from eNOS-/- mice restored the decreased neurosphere formation, proliferation, neurite outgrowth, and telomerase activity in cultured eNOS(-/-) SVZ neurospheres. SVZ explant cell migration also was significantly decreased in eNOS-/- mice compared with wild-type mice. These data indicate that eNOS is not only a downstream mediator for VEGF and angiogenesis but also regulates BDNF expression in the ischemic brain and influences progenitor cell proliferation, neuronal migration, and neurite outgrowth and affects functional recovery after stroke.
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PMID:Endothelial nitric oxide synthase regulates brain-derived neurotrophic factor expression and neurogenesis after stroke in mice. 1574 63

Inhibitors of HMG-CoA reductase (statins) are potent cholesterol-lowering drugs. Large clinical trials have shown that statins reduce the incidence of cerebrovascular events, which might be surprising because cholesterol is not an established risk factor for stroke. In addition to their cholesterol-lowering properties, statins exert a number of pleiotropic, vasculoprotective actions that include improvement of endothelial function, increased nitric oxide (NO) bioavailability, antioxidant properties, inhibition of inflammatory responses, immunomodulatory actions, regulation of progenitor cells, and stabilization of atherosclerotic plaques. In fact, statins augment cerebral blood flow and confer significant protection in animal models of stroke partly via mechanisms related to the upregulation of endothelial nitric oxide synthase. Retrospective clinical evidence suggests that long-term statin administration may not only reduce stroke risk but also improve outcome. Early secondary prevention trials are underway to test the hypothesis that statin treatment initiated immediately after an event improves short-term outcome. Lastly, recent evidence suggests that sudden discontinuation of statin treatment leads to a rebound effect with downregulation of NO production. Withdrawal of statin treatment may impair vascular function and increase morbidity and mortality in patients with vascular disease.
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PMID:Statins and stroke. 1581 80

Amyloid beta-peptide (Abeta) cytotoxicity, the hallmark of Alzheimer's disease, implicates oxidative stress in both neurons and vascular cells, particularly endothelial cells. Consequently, antioxidants have shown neuroprotective activities against Abeta-induced cytotoxicity. Among the different antioxidants used in both in vitro and in vivo studies, 17beta-oestradiol (E2) has garnered the most attention. Oestrogen attenuated Abeta(E22Q)-induced toxicity in neurons but failed to protect endothelial cells. Here we show that E2-mediated activation of endothelial nitric oxide synthase (eNOS) increases the production of nitric oxide (NO), which, under Abeta(E22Q)-induced oxidative damage, results in the formation of peroxynitrite and increased nitration of tyrosine residues. Inhibition of eNOS prevents nitrotyrosination and permits E2-mediated protection against Abeta(E22Q) on endothelial cells. The main nitrotyrosinated proteins in the presence of E2 and Abeta(E22Q) were identified by MALDI-TOF mass spectrometry. These proteins are key players in the regulation of energy production, cytoskeletal integrity, protein metabolism and protection against oxidative stress. Our data highlight the potential damaging consequences of E2 in vascular disorders dealing with oxidative stress conditions, such as cerebral amyloid angiopathy, stroke and ischaemia-reperfusion conditions.
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PMID:Lack of oestrogen protection in amyloid-mediated endothelial damage due to protein nitrotyrosination. 1581 16

Fabry disease is associated with increased risk of premature stroke and presumptive ischemic cerebral lesions. In 57 consecutive patients, 35% of whom had lesions on brain MRI, the authors found that genotypes of polymorphisms G-174C of interleukin-6, G894T of endothelial nitric oxide synthase, factor V G1691A mutation, and the A-13G and G79A of protein Z were all significantly associated with cerebral lesions. These findings suggest that these proteins modulate Fabry cerebral vasculopathy.
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PMID:Effect of genetic modifiers on cerebral lesions in Fabry disease. 1660 44

Rho-kinase has been identified as one of the effectors of the small GTP-binding protein Rho. Accumulating evidence has demonstrated that Rho/Rho-kinase pathway plays an important role in various cellular functions, not only in vascular smooth muscle cell (VSMC) contraction but also in actin cytoskeleton organization, cell adhesion and motility, cytokinesis, and gene expressions, all of which may be involved in the pathogenesis of cardiovascular disease. At molecular level, Rho-kinase upregulates various molecules that accelerate inflammation/oxidative stress, thrombus formation, and fibrosis, whereas it downregulates endothelial nitric oxide synthase. The expression of Rho-kinase itself is mediated by protein kinase C/NF-kappaB pathway with an inhibitory and stimulatory modulation by estrogen and nicotine, respectively. At cellular level, Rho-kinase mediates VSMC hypercontraction, stimulates VSMC proliferation and migration, and enhances inflammatory cell motility. In animal studies, Rho-kinase has been shown to be substantially involved in the pathogenesis of vasospasm, arteriosclerosis, ischemia/reperfusion injury, hypertension, pulmonary hypertension, stroke and heart failure, and to enhance central sympathetic nerve activity. Finally, in clinical studies, fasudil, a Rho-kinase inhibitor, is effective for the treatment of a wide range of cardiovascular disease, including cerebral and coronary vasospasm, angina, hypertension, pulmonary hypertension, and heart failure, with a reasonable safety. Thus, Rho-kinase is an important therapeutic target in cardiovascular medicine.
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PMID:Rho-kinase is an important therapeutic target in cardiovascular medicine. 1600 41

We examined the age-related changes in cardiac expression of angiogenic molecules during the development of cardiac remodeling in stroke-prone spontaneously hypertensive rats (SHRSP) in comparison with those in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Vascular endothelial growth factor (VEGF) was highly upregulated in SHRSP aged 20 weeks compared with the same age of WKY, but it was downregulated at 40 weeks. On the other hand, KDR, an angiogenic receptor of VEGF, and endothelial nitric oxide synthase, which is important in the VEGF-mediated angiogenic pathway, were markedly downregulated in SHRSP from 20 weeks of age. Such age-related changes in their expression levels seen in SHRSP were quite different from those in SHR. In both SHR and SHRSP, transforming growth factor-beta1 (TGF-beta1) expression was increased with age, although SHRSP showed more marked upregulation. Cardiac remodeling in SHRSP was characterized by decreased coronary capillary density, cardiomyocyte hypertrophy, and cardiac fibrosis. We conclude that, in addition to overexpression of TGF-beta1, which appears to play a pivotal role in promoting cardiac hypertrophy and fibrosis, a defect of the VEGF-KDR system could result in impaired physiologic coronary angiogenesis in SHRSP, contributing to cardiac deteroration associated with myocardial ischemia in this malignant hypertensive model.
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PMID:Age-related changes in cardiac expression of VEGF and its angiogenic receptor KDR in stroke-prone spontaneously hypertensive rats. 1601 Sep 73

Atherosclerosis is a multifactorial condition that can result in cardiovascular disease. Statin therapy is thought to mediate cardioprotective effects that influence endothelial function, inflammatory responses, plaque stability and thrombus formation, processes involved in atherosclerosis. Although reduction in low-density lipoprotein cholesterol (LDL-C) potentially plays a role in all of these effects, several lines of evidence also implicate nonlipidmediated 'pleiotropic' effects. For example, statin therapy confers a lower risk for coronary heart disease than placebo in patients with comparable serum cholesterol levels, and confers a greater magnitude of clinical benefit than expected based on LDL-C levels alone. Moreover, while nonstatin lipid-lowering therapy does not necessarily reduce stroke risk, statins have shown a significant reduction in stroke. Statins exert their pleiotropic effects, in part, by improving endothelial function via up-regulation of endothelial nitric oxide synthase enzyme activity. Markers of inflammation such as high sensitivity C-reactive protein have been also shown to add further prognostic information about patients at risk of cardiovascular disease who may benefit from statin therapy. Further studies are still needed to determine whether statins have direct effects on inflammatory pathways.
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PMID:Statins: potent vascular anti-inflammatory agents. 1603 95

Local adenoviral (Ad)-mediated gene transfer to the carotid artery of the stroke-prone spontaneously hypertensive rat (SHRSP) is successful in improving endothelial function. Here we explored the potential of systemic delivery of Ad encoding endothelial nitric oxide synthase (AdeNOS) to prevent elevation of blood pressure in the SHRSP using both nontargeted and vector targeting approaches. Systemic administration of nontargeted AdeNOS failed to modify the rise in blood pressure in SHRSP when administered during the 12th week of age (n = 5, P = 0.088, F = 3.0), an effect likely to result from sequestration of Ad by the liver. Rerouting Ad transduction using a bispecific antibody (anti-ACE/anti-Ad capsid, Fab9B9) that blocks Ad binding to the coxsackie and adenovirus receptor and simultaneously retargets AdeNOS to the angiotensin-converting enzyme resulted in efficient eNOS overexpression in the lung vasculature and a sustained hypotensive effect (n = 5, P = 0.007, F = 7.9). This study highlights the importance of vector targeting to achieve therapeutic gain and represents the first such study in cardiovascular gene therapy.
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PMID:Targeting endothelial cells with adenovirus expressing nitric oxide synthase prevents elevation of blood pressure in stroke-prone spontaneously hypertensive rats. 1604

Hyperhomocysteinemia is a risk factor for cardiovascular disease and stroke. During the last decade, considerable progress in delineating the mechanisms that underlie the atherogenic effects of hyperhomocysteinemia has been achieved through the use of experimental animal models. Among the most informative animal models are those that use genetic and dietary approaches to produce hyperhomocysteinemia in mice. Recent findings demonstrate that hyperhomocysteinemia can accelerate the development of atherosclerosis in susceptible models such as the apolipoprotein E-deficient mouse. Hyperhomocysteinemia also is a potent inducer of endothelial dysfunction, particularly in small vessels such as cerebral arterioles. Mechanisms of endothelial dysfunction may include inhibition of endothelial nitric oxide synthase by its endogenous inhibitor, asymmetric dimethylarginine, and oxidative inactivation of nitric oxide mediated by upregulation of prooxidant enzymes and downregulation of antioxidant enzymes. There also is good evidence from animal models that hyperhomocysteinemia produces endoplasmic reticulum stress, which may contribute to atherosclerosis and endothelial dysfunction by activating signal transduction pathways leading to inflammation, oxidative stress, and apoptosis.
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PMID:Mechanisms of the atherogenic effects of elevated homocysteine in experimental models. 1604 68


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