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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The authors investigated the dehydrogenase histochemistry of arterioles on 22 muscular biopsies from 14 male and 8 female patients with different clinical forms of atherosclerosis, and in 5 controls. There was a diminution with age of all the enzymes studied. In 3 of 6 cases with pathological lesions (thickening of endothelium, fragmentation of the internal elastic lamina, thrombosis) there was a regional diminution of NADH-diaphorase and NADPH-diaphorase activities parallel with an increase of the reaction for lactic dehydrogenase and glutamate dehydrogenase in the muscular cells and endothelium.
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PMID:Histoenzymology of muscular arterioles. 81 50

Nitric oxide (NO) is an important intercellular signaling molecule synthesized in diverse human tissues by proteins encoded by a family of NO synthase (NOS) genes. The similarity of sequence and cofactor binding sites has suggested that the NOS genes may also be related to cytochrome P450 reductase, as well as to plant and bacterial oxidoreductases. Endothelial NOS activity is a major determinant of vascular tone and blood pressure, and in several important (and sometimes hereditary) disease states, such as hypertension, diabetes, and atherosclerosis, the endothelial NO signaling system appears to be abnormal. To explore the relationship of the endothelial NOS gene to other similar genes, and to delineate the genetic factors involved in regulating endothelial NOS activity, we isolated the human gene encoding the endothelial NOS. Genomic clones containing the 5' end of this gene were identified in a human genomic library by applying a polymerase chain reaction (PCR)-based approach. Identification of the human gene for endothelial NOS (NOS3) was confirmed by nucleotide sequence analysis of the first coding exon, which was found to be identical to its cognate cDNA. The NOS3 gene spans at least 20 kb and appears to contain multiple introns. The transcription start site and promoter region of the NOS3 gene were identified by primer extension and ribonuclease protection assays. Sequencing of the putative promoter revealed consensus sequences for the shear stress-response element, as well as cytokine-responsive cis regulatory sequences, both possibly important to the roles played by NOS3 in the normal and the diseased cardiovascular system.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Isolation and chromosomal localization of the human endothelial nitric oxide synthase (NOS3) gene. 751 68

Vascular endothelial cells produce various biologically active factors regulating blood pressure, coagulation, and possibly cell growth of the vascular wall. Of the factors, nitric oxide (NO) has been the object of attention because of its quite simple molecular structure and variety of biological functions. In the present review, we focused on the physiologic and pathologic aspects of NO in hypertension. In experimental animals, both acute and chronic inhibition of NO synthase (NOS) with arginine derivatives produce a significant rise in blood pressure, indicating that tonic production of NO regulates basal vascular tonus. The chronic hypertension caused by NOS inhibitor is associated with cardiac hypertrophy and renal insufficiency. Sodium retention, though transient, and the plasma and tissue renin/angiotensin system in addition to the reduced production of NO have been implicated in the development of hypertension. Hypertension and the associated target organ failure can be reversed by co-administration of L-arginine or blockades of the renin/angiotensin system. Studies in which L-arginine as the substrate of NO or NOS inhibitor was administered demonstrated an important role of NO in the regulation of tonic vascular tonus also in normal subjects. In hypertensive subjects, however, endothelium-dependent vasorelaxation and production of NO are impaired, possibly due to a deficiency of L-arginine and/or a disorder of its utilization. Recent advances in the methods of detecting NO enabled us to demonstrate its diminished production from endothelial cells of hypertensive rats in vitro, although no definite biochemical evidence has been obtained in hypertensive subjects. The endothelial dysfunction, however, is not a primary cause of hypertension but a secondary result since it is commonly observed in various types of hypertension and can be reversed by correcting the blood pressure. Other common diseases including atherosclerosis and diabetes mellitus are also associated with similar abnormalities of the endothelium. NO has anti-atherogenic actions: inhibition of platelet functions and proliferation of vascular smooth muscle cells. Therefore, potentiation of endogenous NO and/or supplement of exogenous NO donors could be novel therapeutic approaches for the treatment of hypertension and atherosclerosis, while potential adverse effects of NO including cytotoxicity, immunosuppressibility, and hypotensive shock should be taken into account.
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PMID:[Clinical significance of nitric oxide in hypertension]. 752 65

Endothelial and platelet generation of nitric oxide (NO) plays an important role in the regulation of hemostasis. Alterations in NO biosynthesis are described in atherosclerosis. We have investigated the NO pathway in megakaryocytes and platelets from patients with atherosclerosis and age-matched control subjects. Megakaryocytes and platelets were isolated from patients with severe coronary atherosclerosis (n = 19) and normal coronary arteries (n = 9) as demonstrated by selective angiography. Constitutive (Ca(2+)-dependent) and inducible (Ca(2+)-independent) NO synthase (cNOS and iNOS, respectively) activities were measured by using the citrulline assay and by immunostaining techniques using an anti-peptide antibody to iNOS. Megakaryocytes from patients with atherosclerosis expressed significantly greater amounts of iNOS (1.28 +/- 0.46 pmol citrulline.mg-1.min-1) than cNOS (0.29 +/- 0.40 pmol.mg-1.min-1). In contrast, megakaryocytes from patients with normal coronary arteries expressed significantly more cNOS (1.48 +/- 0.23 pmol.mg-1.min-1) than iNOS (0.49 +/- 0.40 pmol.mg-1.min-1). Platelets isolated from both groups showed no significant difference in cNOS expression, and no iNOS was seen in either group. Immunostaining confirmed the presence of the iNOS in megakaryocytes. These results suggest there is a link between the expression of iNOS in the megakaryocyte and atherosclerosis.
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PMID:Megakaryocytes from patients with coronary atherosclerosis express the inducible nitric oxide synthase. 753 28

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

Nitric oxide (NO), derived from the vascular endothelium and other cells of the cardiovascular system, has important roles in physiological regulation of blood flow and may have pathophysiological functions in cardiovascular disease. The mechanisms involved in NO-induced vasodilatation and cytotoxicity are briefly reviewed in the context of inflammatory reactions and cardiovascular function. Although NO can hyperpolarize vascular smooth muscle, activation of the endothelium can induce hyperpolarization and vasodilatation by other means. Endogenous inhibitors of NO generated by leucocytes may compromise blood flow distribution after ischaemia and reperfusion injury. Chronic heart failure is associated simultaneously with impairment of endothelium-dependent vasodilatation and with excess production of NO via the inducible NO synthase (iNOS), although it is unclear whether the latter ameliorates or exacerbates ventricular dysfunction. Excess NO production is also one of the earliest signs of transplant rejection, and suppression of iNOS expression by immunosuppressant drugs such as cyclosporin A might be one means by which these drugs protect allografts. Disturbances in the activity of NOS isoforms in the artery wall also accompany the development of atherosclerosis, providing conditions propitious for vasospasm and thrombosis. Reversing the NO defects with therapeutic agents, including angiotensin converting enzyme (ACE) inhibitors, offers promise in protecting against some manifestations of vascular disease.
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PMID:Endogenous nitric oxide in cardiovascular disease and transplantation. 754 30

Hypercholesterolemia, before atherosclerosis, is known to reduce agonist- (e.g., acetylcholine) mediated nitric oxide (NO) production within 2 weeks of a cholesterol-enriched diet. However, no data exist on the effect of hypercholesterolemia on the basal release of NO from blood vessels. We studied the basal release of NO in rabbit coronary arteries by addition of the NO synthase blocker NG-nitro-L-arginine-methyl ester (L-NAME). Basal release of NO was markedly attenuated 2 weeks after introduction of a 0.5% cholesterol addition to the diet. One week later, the adherence of neutrophils to the coronary endothelium was significantly enhanced (i.e., threefold; p < 0.01 different from control). The increased adhesiveness could be attributed to enhanced endothelial adhesion rather than to changes in the properties of the leukocytes. Both phenomena could be reversed by addition of L-arginine to isolated coronary arteries. Administration of 10 mg/day lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, markedly attenuated both the reduced basal NO production and the increased adhesiveness of the endothelium. These results support the concept that NO is an important protective agent produced by the endothelium to preserve the integrity of the endothelium and may protect it against atherogenesis.
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PMID:Decreased basal nitric oxide release in hypercholesterolemia increases neutrophil adherence to rabbit coronary artery endothelium. 768 5

Nitric oxide (NO), which accounts for the biological properties of endothelium-derived relaxing factor, is generated by NO synthase (NOS). The vascular endothelium contains two types of NOS: one is constitutively expressed (cNOS), and the other is inducible. Endothelium-mediated vasorelaxation is impaired in atherosclerotic vessels. To determine whether tumor necrosis factor (TNF)-alpha, which is commonly found in atherosclerotic lesions, has an effect on NOS message, we measured cNOS mRNA levels in TNF-treated human umbilical vein endothelial cells (HUVECs) by RNA blot analysis with a cNOS cDNA probe. TNF-alpha markedly reduced cNOS mRNA levels in HUVECs in a dose- and time-dependent manner. In response to 3 ng/mL TNF-alpha, cNOS mRNA levels began to decrease at 4 hours and diminished to only 5% of control levels at 24 hours. As little as 0.1 ng/mL TNF-alpha reduced cNOS mRNA levels by 50%. This reduction in cNOS message in response to TNF-alpha depended on protein synthesis as it was blocked by cycloheximide. In nuclear runoff experiments, TNF-alpha did not change the rate of cNOS gene transcription. cNOS mRNA is very stable under basal conditions, with a half-life of 48 hours; however, treatment with TNF-alpha shortened this half-life to 3 hours. TNF-alpha thus appears to decrease cNOS mRNA levels by increasing the rate of mRNA degradation. TNF-induced reductions in cNOS mRNA levels may have an important effect on impaired endothelium-mediated vasorelaxation in atherosclerosis.
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PMID:Tumor necrosis factor downregulates an endothelial nitric oxide synthase mRNA by shortening its half-life. 768 52

Nitric oxide is synthesised from an amino acid, L-arginine, by a family of enzymes called nitric oxide (NO) synthase, by most cells in the vessel wall. In healthy vessels, the production of NO is due to the constitutive and calcium dependent NO synthase present in the endothelial cells. On the other hand, when the vascular system is diseased and defense mechanisms are activated, the mediators of inflammatory and immunitary reactions induce an NO synthase non-responsive to calcium which produces large quantities of NO in most of the cells of the vessel wall. Nitric oxide is a liposoluble radical with a short half-life. It plays a central role in the regulation of the motricity and proliferation of blood vessels and in the interaction of the blood cells with the vessel wall. An inadequate production of nitric oxide could play a role in many vascular diseases such as hypertension, atherosclerosis, restenosis or vascular hyporeactivity associated with septicaemic shock.
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PMID:[Nitric oxide and homeostasis of the smooth vascular muscle]. 769 33

Endothelial function of epicardial arteries and coronary resistance vessels, as well as endothelial dysfunction and clinical symptoms of coronary artery disease and their therapeutic implications are reviewed including the presentation of the author's own results. Coronary endothelial vasodilator dysfunction represents a fundamental functional disturbance in vascular biology with the development of atherosclerosis. This functional alteration in coronary vascular reactivity appears to play an important integral part in the clinical presentation of coronary artery disease. Humoral and neuronal factors in favour of vasoconstrictor influences affect the balance between myocardial oxygen supply and demand, thus, facilitating the manifestation of myocardial ischemia. In order to identify more selective therapies the potential mechanisms underlying an impaired release or activity of EDRF/NO must be considered. Dysfunction of the endothelial L-arginine/NO pathway may involve decreased activity of NO synthase, increased inactivation of NO formed from its precursor L-arginine, impaired signal transduction mechanisms and reduced intracellular availability of L-arginine. Currently, initial therapeutic strategies include the supplementation of L-arginine, the use of antioxidants, as well as ACE-inhibitors. ACE-inhibitors have been shown not only to reduce vascular tone (and hypertrophy) by inhibition of angiotensin II formation, but also by increasing the endothelial production of NO and prostacyclin most likely due to the local accumulation of endothelium-derived bradykinin. Thus, ACE-inhibition appears to provide the potential to improve endothelial NO synthesis. Indeed, study results demonstrate that chronic ACE-inhibition is associated with an increased coronary blood flow response to acetylcholine suggesting an improvement in endothelial vasodilator functioning of coronary resistance vessels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Coronary endothelial vasodilator dysfunction: clinical relevance and therapeutic implications. 785 84


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