Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Significant advances have been made in our understanding of the role of the vascular endothelium in preventing thrombosis and in decreasing vascular spasm. The endothelium provides a surface receptor, thrombomodulin, that binds thrombin. In this form, thrombin loses its ability to clot fibrinogen or to aggregate platelets, but is able to activate protein C. In its activated state, protein C is able to act as an inhibitor of coagulation by virtue of its proteolytic destruction of Factors Va and VIIIa. Congenital deficiency of protein C is associated with early and recurrent thrombosis. The discovery that the endothelium is responsible for the production of a short-acting inhibitor of smooth-muscle contraction (EDRF) was a remarkable advance. One of the EDRF substances has been demonstrated to be NO, which has inhibitory effects on both smooth muscle and blood platelets. Activity of EDRF appears to be diminished or lost as a consequence of atherosclerosis, and stimuli that cause vasodilation via the EDRF pathway in normal vessels cause vasoconstriction in atherosclerotic arteries. Regression of atherosclerosis in experimental animals appears to be associated with restoration of EDRF activity.
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PMID:The endothelium, platelets, and coronary vasospasm. 264 64

The endothelium releases the powerful vasodilator and antiaggregatory substance, EDRF, both under basal conditions and upon stimulation by a wide variety of agents. Endothelial injury or dysfunction may play an important role in the spasmogenicity of the coronary artery, although other possible alterations related to atherosclerosis should also be considered. Among the possible stimuli, aggregating platelets are important as a source of vasoconstrictor substances. The endothelium may also produce the vasoactive substances EDHF and EDCF(s). Their pathophysiologic significance remains to be determined.
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PMID:Endothelium-derived relaxing factor and coronary vasospasm. 266 Oct 51

Endothelial cells can release substances which profoundly affect vascular tone and platelet function. The inhibitory substances include endothelium-derived relaxing factor (EDRF or nitric oxide), prostacyclin and probably an endothelium-derived hyperpolarizing factor. Endothelin is a potent vasoconstrictor peptide released from endothelial cells. Under certain conditions, the endothelium can also produce angiotensin II, thromboxane A2 and a cyclooxygenase-dependent endothelium-derived contracting factor. In normal arteries, the effects of EDRF appear to dominate. In diseased arteries, the release and action of EDRF is impaired and that of endothelium-derived contracting factors is increased. Hyperlipidaemia, atherosclerosis and hypertension reduce endothelium-dependent relaxations. Hypoxia inhibits the release of EDRF and prolonged ischaemia severely impairs the response. Regenerated endothelium at sites of mechanical injury exhibits selective defects in response to aggregating platelets. The more effective release of EDRF in arterial compared with venous bypass grafts further suggests an involvement of the factor in preventing vascular occlusion. Therapeutic interventions with specific drugs and diets can augment the impaired endothelium-dependent relaxation of diseased arteries. Thus, functional changes of the endothelium in coronary artery disease may be an important factor in the development of vasospasm, ischaemia and thrombosis.
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PMID:Endothelium-derived relaxing and contracting factors: potential role in coronary artery disease. 268 Apr 93

The antiplatelet action of PGE1 was the basic concept for introducing this substance into clinical therapy of atherosclerosis. However, in the meanwhile a variety of other mechanisms have been discovered, which might be of importance, especially concerning the long-term benefit seen after treatment with PGE1, such as stabilization of endothelial lining, reflected by a decreased number of circulating endothelial cells and a decreased thrombogenicity (potentiated by endogenous EDRF-release), an inhibitory action on smooth muscle cells of the vessel wall such as decrease in mitotic and proliferative activity associated with a diminished extracellular matrix formation, an increase in fibrinolytic capacity, beneficial effects on white and red blood cells and some beneficial effects on the lipid metabolism by decreasing the arterial wall cholesterol content and upregulation of LDL-receptors as well as a moderate drop in serum cholesterol, seen in severe hypercholesterolemics only. It is assumed, that especially the vascular effects together with the hypolipidemic actions of PGE1 might be of major importance underlying the long-term benefit.
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PMID:Pathomechanisms of atherosclerosis beneficially affected by prostaglandin E1 (PGE1)--an update. 269 1

The social importance of endocrinology is apparent from an analysis of the prevalence of endocrinopathies in the CSSR. They affect (incl. diabetes and eufunctional goitre) some 10% of the population. The author submits a brief account of the development of knowledge of hormones and of Nobel prizes awarded for hormone research. On some examples he demonstrates the importance of endocrinology for other medical disciplines: the interrelationship of stress and infectious reactions via interleukin 1, the discovery of a series of new growth and immune factors; the participation TNF (cachectin, tumour necrosis factor) in pathological processes (tumours, atherosclerosis); vasoactive peptides EDRF (endothelium derived relaxation factor), endothelin (vasoconstriction), GM-CSF (granulocyte-macrophage colony stimulating factor) in treatment of radiation sickness and adjuvans in chemotherapy; interleukins. These new peptide hormones are words in the complex cellular signal alphabet the importance of which in the control of cellular activities we are beginning to understand.
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PMID:[Endocrinology: lessons from the past, hopes for the future]. 271 85

Recent pharmacologic evidence supports the importance of the integrity of the endothelium in modulating vascular reactivity. The endothelial cells produce one or more endothelium derived relaxing factor(s) or EDRF that cause relaxation of vascular smooth muscle cells through production of cyclic guanosine monophosphate (GMP) and subsequent activation of protein kinase. While the molecular pharmacology of vascular relaxation is now well defined and numerous factors have been identified that inhibit or stabilize EDRF, the chemical identity of EDRF still is uncertain. Nitric oxide appears to be one such EDRF. Alterations in vasoreactivity observed during surgical manipulation, trauma, inhalational anesthesia, atherosclerosis, and other disease states can now be explained by their influence on the endothelial cells and EDRF. Further, it is now clear that nitrovasodilators act directly on the vascular smooth muscle cell to produce biological intermediates that mimic the endogenous factors. While anesthesiologists and critical care physicians have traditionally focused on hormonal and nervous system control of vascular reactivity, the effects of various drugs and manipulations on EDRF appear to be of clinical importance. In this manuscript we review the pharmacology of EDRF and of exogenous nitrovasodilators with particular reference to factors that can modulate vasoreactivity.
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PMID:Endothelium-dependent vascular smooth muscle control. 307 30

Endothelial cells can produce at least 3 substances which cause relaxation of vascular smooth muscle: (1) endothelium-derived nitric oxide (NO, which is secreted not only toward the underlying vascular smooth muscle but also into the blood vessel lumen). NO also has a physiological role at the interface between the endothelial cells and the blood content; in particular, NO inhibits the adhesion of platelets and leukocytes to the endothelium. (2) Endothelium-derived hyperpolarizing factor, presumably a labile metabolite of arachidonic acid formed through the P-450 pathway, which appears to act on smooth muscle by being one of the few physiologic openers of the potassium channels. (3) Prostacyclin, which can be considered as an endothelium-derived relaxing substance, given its vasodilator activity and its primarily endothelial origin. One of the main factors modulating the release of these EDRFs is the shear stress of blood on the arterial wall, which explains why flow-induced vasodilation is endothelium-dependent in the intact organism. The peptide bradykinin is a potent stimulus for EDRF release. The normal lifespan of an adult human endothelial cell is some 30 years, after which aging takes its toll and the cells must be replaced. The regenerated cells lose some of their ability to release EDRF, in particular in response to platelet aggregation and thrombin. Finally, in hypertension and atherosclerosis, a decrease in endothelium-dependent relaxation is obvious in response to a variety of stimuli. All converting enzyme inhibitors tested so far share a potentiating effect on endothelium-dependent relaxation to bradykinin, and augmented local production of bradykinin may help to explain the acute vasodilator properties of these compounds.
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PMID:Endothelium-derived relaxing factors and converting enzyme inhibition. 748 85

To evaluate the significance of repeated denudation injury in progression of atherosclerosis, we performed a single and then a second balloon denudation on the rabbit carotid arteries. Morphological examinations and organ chamber experiments were performed, and the results were compared. On morphological examinations, reendothelialization was almost completed in 2 wk after redenudation, whereas it required 6 wk after a single denudation. Intimal thickening progressed after redenudation. Organ chamber experiments showed that contractile responses and endothelium-independent relaxation remained unchanged after redenudation. Endothelium-dependent relaxations to acetylcholine, ADP, and substance P decreased progressively by repeating denudation. These relaxation responses were inhibited by NG-nitro-L-arginine, hemoglobin, and methylene blue and were considered to be associated with the production and/or release of endothelium-derived relaxing factor-nitric oxide (EDRF-NO). The diffusion barrier mechanism for the decreased endothelium-dependent relaxations was ruled out using sandwich experiments. In conclusion, repeated endothelial denudation caused progression of intimal thickening and acceleration of endothelial regeneration, and repeated endothelial regeneration resulted in progressively less production and/or release of EDRF-NO.
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PMID:Repeated endothelial removal augments intimal thickening and attenuates EDRF release. 751 59

Key discoveries in the past decade have revealed that the vascular endothelium is an important regulatory organ that is involved in maintaining cardiovascular homeostasis in health and contributes significantly to the pathomechanism of several cardiovascular diseases. Occupying a strategically important location between circulating blood and tissues and having the ability to respond to changes in its physical, chemical, and humoral environment by the production of a host of biologically active substances, the normal endothelium modulates the tone of underlying vascular smooth muscle, maintains a nonadhesive luminal surface, and mediates hemostasis, cellular proliferation, and inflammatory and immune mechanisms in the vascular wall. Modulation of smooth-muscle tone is mediated by the synthesis release of endothelium-derived relaxing [PGI2, EDRF(NO), and EDHF] and contracting factors (arachidonic acid metabolites, endothelin-1, and angiotensin II). Anticoagulant, fibrinolytic, and antithrombotic properties contribute to the maintenance of the fluidity of blood. Injury or activation (by cytokines) of endothelial cells disrupts these normal regulatory mechanisms and results in morphologic and functional alterations (phenotypic changes) commonly defined as endothelial dysfunction. Clinically, the "syndrome" of endothelial cell dysfunction can be described as generalized or localized vasospasm, thrombosis, atherosclerosis, and restenosis. Although its importance is clearly established, no drugs used today were originally targeted for the treatment of endothelial dysfunction. Recent studies, however, showed that some existing therapies (e.g., angiotensin-converting enzyme inhibitors) may protect the endothelium. Novel diagnostic techniques and innovative therapeutic strategies, based on the already known molecular mechanisms of endothelial dysfunction, are briefly outlined. Further knowledge of the pathobiology of the impaired endothelium will contribute to unraveling some of the remaining mysteries of many cardiovascular diseases and will enable us to design novel therapies to prevent and treat them.
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PMID:The role of endothelium in cardiovascular homeostasis and diseases. 752 67

Endothelium-derived relaxing factor/nitric oxide (EDRF/NO) is produced by the vascular wall and is a key modulator of vascular tone and blood pressure. Since reduced EDRF/NO release from the endothelium is a major key event in the development of atherosclerosis, we investigated the effect of cholesterol on endothelial cell particulate (membrane-bound) NO synthase activity. Low concentrations (up to 0.2 mM) of liposomal cholesterol progressively activated plasma membrane-bound NO synthase. Increasing cholesterol concentration above that which maximally stimulated enzyme activity produced a progressive inhibition with respect to the control value. In time course experiments using endothelial cell plasma membranes enriched with cholesterol, changes in NO production were followed by analogous changes in soluble guanylate cyclase activity (sGC). N-Monomethyl-L-arginine (L-NMMA) (1 mM) inhibited particulate NO synthase activity at all cholesterol concentrations used with subsequent decreases in cGMP production. Egg lecithin liposomes (free of cholesterol) had no effect on NO synthase activity. A three-fold increase in superoxide (O2-) and a 2.5-fold increase in NO formation followed by an eight-fold increase in peroxynitrite (ONOO-) production by cholesterol-treated microsomes isolated from endothelial cells was observed, one which rose further up to eight-fold in the presence of superoxide dismutase (SOD) (10 U/mL). Cholesterol had no effect on Lubrol-PX solubilized membrane-bound NO synthase or on cytosolic (soluble) NO synthase activities of endothelial cells. Cholesterol modulated lipid fluidity of plasma membranes labelled with 1,6-diphenyl-1,3,5-hexatriene (DPH) as indicated by the steady state fluorescence anisotropy [(ro/r)-1]-1. Arrhenius plots of [(ro/r)-1]-1 indicated that the lipid phase separation of the membranes at 26.2 +/- 1.5 degrees was elevated to 34.4 +/- 1.9 degrees in cholesterol-enriched membranes, consistent with a general decrease in membrane fluidity. Cholesterol-enriched plasma membranes treated with egg lecithin liposomes showed a lipid phase separation at 27.5 +/- 1.6 degrees, indicating the reversible effect of cholesterol on membrane lipid fluidity. Arrhenius plots of NO synthase activity exhibited break point at 26.9 +/- 1.8 degrees which rose to 35.6 +/- 2.1 degrees in 0.5 mM cholesterol-treated plasma membranes and decreased to 21.5 +/- 1.4 degrees in plasma membranes treated with 0.2 mM cholesterol. The allosteric properties of plasma membrane-bound NO synthase inhibited by Mn2+ (as reflected by changes in the Hill coefficient) were changed by cholesterol, consistent with modulations of the fluidity of the lipid microenvironment of the enzyme.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Modulation of particulate nitric oxide synthase activity and peroxynitrite synthesis in cholesterol enriched endothelial cell membranes. 754 Mar 91


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