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

Smoking is a significant independent risk factor for cardiovascular disease and is a leading cause of structural and functional alterations of the cardiovascular system. Most clinical and experimental investigations of the pathophysiology of cigarette smoking have studied the effects of smoke as a whole, while a few studies focused on specific components of cigarette smoke, e.g. nicotine and carbon monoxide, which are only 2 of the more than 4,000 different chemicals present in cigarette smoke. The findings point to some discrepancies when the effects of whole smoke are compared to nicotine alone, while there is almost uniform agreement that both active and passive smoking have detrimental effects on the cardiovascular system, although a milder effect was suggested for the latter. This review focuses on findings from clinical and experimental studies on the vascular effects of active and passive cigarette smoking and nicotine exposure. The findings are discussed in terms of tissue (conduit vs. resistance arteries and veins), species, age, gender and dosage. Although the exact pathophysiology of cigarette smoking has not been unveiled, cigarette smoking causes injury to the vascular endothelium, produces superoxide anions, reduces production and bioavailability of nitric oxide (NO), increases production and release of endothelin, causes endothelial dysfunction, thrombosis, atherosclerosis, infarction, coronary artery disease (CAD), stroke and death.
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PMID:Structural and functional alteration of blood vessels caused by cigarette smoking: an overview of molecular mechanisms. 1797 94

The endothelium is the common target of all cardiovascular risk factors, and functional impairment of the vascular endothelium in response to injury occurs long before the development of visible atherosclerosis. The endothelial cell behaves as a receptor-effector structure which senses different physical or chemical stimuli that occur inside the vessel and, therefore, modifies the vessel shape or releases the necessary products to counteract the effect of the stimulus and maintain homeostasis. The endothelium is capable of producing a large variety of different molecules which act as agonists and antagonists, therefore balancing their effects in opposite directions. When endothelial cells lose their ability to maintain this delicate balance, the conditions are given for the endothelium to be invaded by lipids and leukocytes (monocytes and T lymphocytes). The inflammatory response is incited and fatty streaks appear, the first step in the formation of the atheromatous plaque. If the situation persists, fatty streaks progress and the resultant plaques are exposed to rupture and set the conditions for thrombogenesis and vascular occlusion. Oxidant products are produced as a consequence of normal aerobic metabolism. These molecules are highly reactive with other biological molecules and are referred as reactive oxygen species (ROS). Under normal physiological conditions, ROS production is balanced by an efficient system of antioxidants, molecules that are capable of neutralizing them and thereby preventing oxidant damage. In pathological states, ROS may be present in relative excess. This shift of balance in favor of oxidation, termed 'oxidative stress', may have detrimental effects on cellular and tissue function, and cardiovascular risk factors generate oxidative stress. Both type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetic patients have mostly been described under enhanced oxidative stress, and both conditions are known to be powerful and independent risk factors for coronary heart disease, stroke, and peripheral arterial disease. Hyperglycemia causes glycosylation of proteins and phospholipids, thus increasing intracellular oxidative stress. Nonenzymatic reactive products, glucose-derived Schiff base, and Amadori products form chemically reversible early glycosylation products which subsequently rearrange to form more stable products, some of them long-lived proteins (collagen) which continue undergoing complex series of chemical rearrangements to form advanced glycosylation end products (AGEs). Once formed, AGEs are stable and virtually irreversible. AGEs generate ROS with consequent increased vessel oxidative damage and atherogenesis. The impressive correlation between coronary artery disease and alterations in glucose metabolism has raised the hypothesis that atherosclerosis and diabetes may share common antecedents. Large-vessel atherosclerosis can precede the development of diabetes, suggesting that rather than atherosclerosis being a complication of diabetes, both conditions may share genetic and environmental antecedents, a 'common soil'.
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PMID:Endothelial dysfunction in normal and abnormal glucose metabolism. 1823 Sep 54

The catecholamine release-inhibitory catestatin [Cts; human chromogranin (Cg) A(352-372), bovine CgA(344-364)] is a vasoreactive and anti-hypertensive peptide derived from CgA. Using the isolated avascular frog heart as a bioassay, in which the interactions between the endocardial endothelium and the subjacent myocardium can be studied without the confounding effects of the vascular endothelium, we tested the direct cardiotropic effects of bovine Cts and its interaction with beta-adrenergic (isoproterenol, ISO) and endothelin-1 (ET-1) signaling. Cts dose-dependently decreased stroke volume and stroke work, with a threshold concentration of 11 nM, approaching the in vivo level of the peptide. Cts reduced contractility by inhibiting phosphorylation of phospholamban (PLN). Furthermore, the Cts effect was abolished by pretreatment with either nitric oxide synthase (N(G)-monomethyl-l-arginine) or guanylate cyclase (ODQ) inhibitors, or an ET(B) receptor (ET(BR)) antagonist (BQ-788). Cts also noncompetitively inhibited the positive inotropic action of ISO. In addition, Cts inhibited the positive inotropic effect of ET-1, mediated by ET(A) receptors, and did not alter the negative inotropic ET-1 influence mediated by ET(BR). Cts action through ET(BR) was further suggested when, in the presence of BQ-788, Cts failed to inhibit the positive inotropism of both ISO and ET-1 stimulation and PLN phosphorylation. We concluded that the cardiotropic actions of Cts, including the beta-adrenergic and ET-1 antagonistic effects, support a novel role of this peptide as an autocrine-paracrine modulator of cardiac function, particularly when the stressed heart becomes a preferential target of both adrenergic and ET-1 stimuli.
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PMID:Catestatin (chromogranin A344-364) is a novel cardiosuppressive agent: inhibition of isoproterenol and endothelin signaling in the frog heart. 1846 47

Elevated total plasma homocysteine is an established risk factor for cardiovascular disease. Experimental evidence suggests that non-protein-bound free homocysteine is particularly hazardous to the vascular endothelium. This study evaluates the predictive role of free plasma homocysteine levels on cardiovascular endpoints in patients with acute coronary syndrome (ACS). In a cohort of 379 hospitalized patients with a diagnosis of myocardial infarction or unstable angina pectoris, total and free plasma homocysteine levels were measured by high performance liquid chromatography. The patients were followed for a median 2.7 years. The primary endpoint was a composite of cardiovascular death, myocardial infarction and stroke during follow-up. Stepwise Cox regression was used for multivariate analysis. Primary outcome events occurred in 82 patients (22%) with a median time to event of 6 months. The unadjusted hazard ratio for a free homocysteine level >4.11 micromol/L was 2.16 (95% confidence intervals [CI] 1.36 to 3.42) compared with the 4 lower quintiles. After adjusting for the covariates the hazard ratio was 2.25 (95% CI 1.41 to 3.58, p = 0.01). Compared with the lower 4 quintiles, patients with a total homocysteine level >22.4 micromol/L had a 2.09-fold higher risk (95% CI 1.31 to 3.35) for an event during follow-up. Adjusted for age, discharge diagnosis, serum creatinine, history of atherothrombotic events, and diabetes mellitus, the adjusted hazard ratio was 1.37 (95% CI 0.83 to 2.25, p = 0.22). In conclusion, plasma free homocysteine levels >4.11 micromol/L are a significant and independent risk factor for recurrent cardiovascular events in patients hospitalized for ACS, although total plasma homocysteine levels have no predictive value.
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PMID:Prognostic value of free plasma homocysteine levels in patients hospitalized with acute coronary syndrome. 1860 9

The endothelium lining blood vessels serves as a barrier against vascular hyperpermeability, and its maintenance is critical to organ health. Inflammatory mediators evoke tissue edema by disrupting the expression of membrane junctional proteins, which mediate binding between endothelial cell membranes. Endothelial cell-cell junctions form a diffusion barrier between the intravascular and interstitial space. To prevent the morbidity and mortality caused by exaggerated vascular permeability associated with pathological states (e.g., inflammatory and hypersensitivity disorders, pulmonary edema, traumatic lung injury, cerebral edema resulting from stroke, and others), it is important to develop therapeutic approaches to stabilize these interendothelial junctions. Vascular endothelial growth factor (VEGF), a potent proangiogenic cytokine, was first described as vascular permeability factor (VPF). Doxycycline, a tetracycline derivative, has been shown to inhibit angiogenesis in both humans and animal models. We now report that oral doxycycline prevents VPF/VEGF-induced vascular permeability, interleukin-2-induced pulmonary edema, and delayed-type hypersensitivity (DTH) in mice. Remarkably, doxycycline also inhibits tumor growth and tumor-associated vascular hyperpermeability. Finally, we show that doxycycline targets the adherens junction in vascular endothelial cells by inducing the total amount of VE-cadherin expression while decreasing the degree of its phosphorylation. The potential of doxycyline as a therapeutic inhibitor of vascular hyperpermeability in human clinical conditions is promising and warrants further studies.
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PMID:Doxycycline induces membrane expression of VE-cadherin on endothelial cells and prevents vascular hyperpermeability. 1860 69

Vascular endothelial injury has multiple elements, and this article focuses on ischemia-related processes that have particular relevance to ischemic stroke. Distinctions between necrotic and apoptotic cell death provide a basic science context in which to better understand the significance of classical core and penumbra concepts of acute stroke, with apoptotic processes particularly prominent in the penumbra. The mitochondria are understood to serve as a reservoir of proteins that mediate apoptosis. Oxidative stress pathways generating reactive oxygen species (ROS) are prominent in endothelial injury, both ischemic and nonischemic, with prominent roles of enzyme- and nonenzymemediated pathways; mitochondria once again have a critical role, particularly in the nonenzymatic pathways generating ROS. Inflammation also contributes to vascular endothelial injury, and endothelial cells have the capacity to rapidly increase expression of inflammatory mediators following ischemic challenge; this leads to enhanced leukocyte-endothelial interactions mediated by selectins and adhesion molecules. Preconditioning consists of a minor version of an injurious event, which in turn may protect vascular endothelium from injury following a more substantial event. Presence of the blood-brain barrier creates unique responses to endothelial injury, with permeability changes due to impairment of endothelial-matrix interactions compounding altered vasomotor tone and tissue perfusion mediated by nitric oxide. Pharmacological protection against vascular endothelial injury can be provided by several of the phosphodiesterases (cilostazol and dipyridamole), along with statins. Optimal clinical responses for protection of brain vascular endothelium may use preconditioning as a model, and will likely require combined protection against apoptosis, ROS, and inflammation.
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PMID:Injuries to the vascular endothelium: vascular wall and endothelial dysfunction. 1864 70

Many mechanisms contribute to the complex pathophysiology of sickle cell disease (SCD), with dysfunction of the vascular endothelium as a unifying theme. Specifically, hemolysis-associated low arginine and nitric oxide (NO) bioavailability, amplified by NO synthase uncoupling, elevated arginase activity, superoxide production, oxidative stress, accumulation of arginine analogs such as asymmetric dimethylarginine, ischemia-reperfusion injury, inflammation, apolipoprotein A-1 depletion, and a hypercoagulable state are significant mechanisms contributing to endothelial dysfunction. Genetic polymorphisms also influence disease severity. Clearly the variable spectrum of disease is the consequence of multiple events and genetic susceptibility that go beyond the occurrence of a single amino acid substitution in the beta globin chain of hemoglobin. Recent studies begin to demonstrate overlap among these seemingly unrelated processes. Impaired NO bioavailability represents the central feature of endothelial dysfunction, and is a common denominator in the pathogenesis of vasculopathy in SCD. The consequences of decreased NO bioavailability include endothelial cell activation, upregulation of the potent vasoconstrictor endothelin-1, vasoconstriction, platelet activation, increased tissue factor, and activation of coagulation, all of which ultimately translate into the clinical manifestations of SCD. Evidence supporting vasculopathy subphenotypes in SCD, including pulmonary hypertension, priapism, cutaneous leg ulceration, and stroke, will be reviewed and relevance to other hemolytic disorders including the thalassemia syndromes will be considered.
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PMID:Mechanisms of vasculopathy in sickle cell disease and thalassemia. 1907 78

Stroke is the second most common cause of death and major cause of disability worldwide. Actual treatment involves surgery and/or thrombolytic drugs, but there is an urgent need for new approaches. Periodic acceleration, a rocking headward to footward movement of the whole body, is a non-invasive method to induce pulsatile shear stress on the vascular endothelium eliciting an enhanced production and secretion of endothelium-derived products such as nitric oxide, prostacyclin, prostaglandin E2, tissue plasminogen activator (tPA), and adrenomedullin. All these products have been shown to protect the brain from ischemic injuries. A rat model of focal brain ischemia was treated with application of periodic acceleration for 3 h immediately after the onset of ischemia. Controls remained static for the same period of time. Brain damage was assessed by magnetic resonance imaging (MRI) and biochemical markers. A significant reduction in brain damage was observed, 7 days post-ischemia, in rocked rats when compared with the static controls, through MRI. Furthermore, rocked animals had significantly lower levels of Beclin 1 and fractin than their static counterparts, and some isoforms of nitric oxide synthase were regulated by periodic acceleration. Our results show that periodic acceleration may provide a novel, affordable, non-invasive therapeutic option for the treatment of stroke.
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PMID:Whole-body periodic acceleration reduces brain damage in a focal ischemia model. 1913 37

Obstructive sleep apnea (OSA) affects 25% of the Western adult population. It is an independent but seldom-recognized risk factor for hypertension, myocardial infarction, stroke, and increased mortality. Patients with OSA experience repetitive episodes of hypoxia/reoxygenation during transient cessation of breathing that promote systemic oxidative stress and inflammation. Vascular endothelial inflammation and enhanced oxidative stress that are reversible with therapy for OSA were recently demonstrated directly in patients with OSA who were free of overt cardiovascular conditions. Vascular endothelial inflammation and enhanced oxidative stress may in part explain the accelerated progression of atherosclerosis in patients with untreated OSA. The present review will focus on indirect and direct evidence of vascular endothelial inflammation and enhanced oxidative stress in patients with OSA. The potential utility of venous endothelial biopsy technique in evaluating the mechanisms that mediate the effects of systemic conditions such as diabetes mellitus, sleep apnea, and obesity on the vascular endothelium will also be discussed.
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PMID:Inflammation, oxidative stress, and the vascular endothelium in obstructive sleep apnea. 1923 54

Atherosclerosis, the primary cause of heart disease and stroke is initiated in the vascular endothelium, and risk factors for its development include environmental exposure to persistent organic pollutants. Caveolae are membrane microdomains involved in regulation of many signaling pathways, and in particular in endothelial cells. We tested the hypothesis that intact caveolae are required for coplanar PCB77-induced up-regulation of monocyte chemoattractant protein-1 (MCP-1), an endothelium-derived chemokine that attracts monocytes into sub-endothelial space in early stages of the atherosclerosis development. Atherosclerosis-prone LDL-R(-/-) mice (control) or caveolin-1(-/-)/LDL-R(-/-) mice were treated with PCB77. PCB77 induced aortic mRNA expression and plasma protein levels of MCP-1 in control, but not caveolin-1(-/-)/LDL-R(-/-) mice. To study the mechanism of this effect, primary endothelial cells were used. PCB77 increased MCP-1 levels in endothelial cells in a time- and concentration-dependent manner. This effect was abolished by caveolin-1 silencing using siRNA. Also, MCP-1 up-regulation by PCB77 was prevented by inhibiting p38 and c-Jun N-terminal kinase (JNK), but not ERK1/2, suggesting regulatory functions via p38 and JNK MAPK pathways. Finally, pre-treatment of endothelial cells with the aryl hydrocarbon receptor (AhR) inhibitor alpha-naphthoflavone (alpha-NF) partially blocked MCP-1 up-regulation. Thus, our data demonstrate that coplanar PCB77 can induce MCP-1 expression by endothelial cells and that this effect is mediated by AhR, as well as p 38 and JNK MAPK pathways. Intact caveolae are required for these processes both in vivo and in vitro. This further supports a key role for caveolae in vascular inflammation induced by persistent organic pollutants.
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PMID:Up-regulation of endothelial monocyte chemoattractant protein-1 by coplanar PCB77 is caveolin-1-dependent. 1926 15


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