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)

Chronic renal failure (CRF) is associated with a 20-fold increased risk of cardiovascular death, two principal mechanisms being: sudden, arrhythmic death associated with left ventricular hypertrophy, and ischaemic heart disease, associated with accelerated atherosclerosis. In recent years, the vascular endothelium has been recognised as a large and complex endocrine organ, with many important physiological functions including the control of vascular tone. Endothelial dysfunction, commonly characterised by reduced production of the vasodilator nitric oxide (NO), is thought to be a key initial event in the development of atherosclerosis and is present in patients with hypertension and hyperlipidaemia. While these cardiovascular risk factors are also prevalent in CRF, other factors more specific to uraemia such as accumulation of homocysteine and asymmetric dimethylarginine (endogenous inhibitor of NO synthase) may impair endothelial function. Modulation of endothelial function in CRF may offer a novel strategy to reduce cardiovascular disease.
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PMID:The vascular endothelium in chronic renal failure. 1085 70

Human coronary and peripheral arteries show endothelial dysfunction in a variety of conditions, including atherosclerosis, hypercholesterolemia, smoking, and hypertension. This dysfunction manifests as a loss of endothelium-dependent vasodilation to acetylcholine infusion or sheer stress, and is typically associated with decreased generation of nitric oxide (NO) by the endothelium. Vitamin C, or ascorbic acid, when acutely infused or chronically ingested, improves the defective endothelium-dependent vasodilation present in these clinical conditions. The mechanism of the ascorbic acid effect is unknown, although it has been attributed to an antioxidant function of the vitamin to enhance the synthesis or prevent the breakdown of NO. In this review, multiple mechanisms are considered that might account for the ability of ascorbate to preserve NO. These include ascorbate-induced decreases in low-density lipoprotein (LDL) oxidation, scavenging of intracellular superoxide, release of NO from circulating or tissue S-nitrosothiols, direct reduction of nitrite to NO, and activation of either endothelial NO synthase or smooth muscle guanylate cyclase. The ability of ascorbic acid supplements to enhance defective endothelial function in human diseases provides a rationale for use of such supplements in these conditions. However, it is first necessary to determine which of the many plausible mechanisms account for the effect, and to ensure that undesirable toxic effects are not present.
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PMID:How does ascorbic acid prevent endothelial dysfunction? 1092 60

Various forms of oxidized low-density lipoproteins (Ox-LDL) are thought to play a major role in the development of atherosclerosis. The lipid components of Ox-LDL present a plethora of proatherogenic effects in in vitro cell culture systems, suggesting that oxidative stress could be an important risk factor for coronary artery disease. However, buried among these effects are those that could be interpreted as antiatherogenic. The present study demonstrates that various oxidants, including oxidized fatty acids and mildly oxidized forms of LDL (MO-LDL), are able to induce catalase (an antioxidant enzyme) expression in rabbit femoral arterial smooth muscle cells (RFASMC), RAW cells (macrophages), and human umbilical vein endothelial cells (HUVEC). In RFASMC, catalase protein, mRNA, and the enzyme activity are increased in response to oxidized linoleic acid (13-hydroperoxy-9,11-octadecadienoic acid [13-HPODE] and 13-hydroxy-9,11-octadecadienoic acid [13-HODE]), MO-LDL, or hydrogen peroxide (H(2)O(2)). Such an increase in catalase gene expression cannot totally be attributed to the cellular response to an intracellular generation of H(2)O(2) after the addition of 13-HPODE or 13-HODE because these agents induce a further increase of catalase as seen in catalase-transfected RFASMC. Taken together with the induction of heme oxygenase, NO synthase, manganese superoxide dismutase (Mn-SOD), and glutathione synthesis by oxidative stress, our results provide yet more evidence suggesting that a moderate oxidative stress can induce cellular antioxidant response in vascular cells, and thereby could be beneficial for preventing further oxidative stress.
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PMID:Lipid peroxides induce expression of catalase in cultured vascular cells. 1094 7

Cardiovascular mortality is excessive in hemodialyzed patients. Observations in atherosclerosis suggest that endothelial dysfunction and impaired nitric oxide (NO) may be involved. However, the relation of endothelial NO to its vascular effects has not been studied conclusively in uremia. Therefore, to study these questions an invasive technique was used in normotensive patients who were on hemodialysis (HD; n = 11) and in matched control subjects (n = 11). Pharmacologic agents were infused into the brachial artery to test the chain of events from NO generation to smooth muscle cell relaxation, measuring forearm blood flow by venous occlusion plethysmography. Glyceroltrinitrate (GTN 1:2.2 nmol/min; GTN 2:4.4; GTN 3:8.8), infused to establish the reaction of the vessel wall to defined doses of NO, caused a reduced response in HD patients (control subjects: 183 +/- 20 [SEM], 246 +/- 26, and 338 +/- 29%; HD patients: 161 +/- 7, 206 +/- 12, and 262 +/- 24%; baseline = 100% for each group, P: = 0.032 by ANOVA). All subsequent data were corrected for this decreased response to defined doses of NO in HD patients. L-arginine (10 mg/min), given to exclude substrate deficiency of NO synthase (NOS), caused no significant changes (control subjects: 108 +/- 4%; HD patients: 103 +/- 4%; P: = NS). Acetylcholine (ACH 1:55 nmol/min; ACH 2:110; ACH 3:220), infused to stimulate endothelial NOS, had a significantly reduced effect in HD patients (control subjects: 246 +/- 32, 340 +/- 40, and 465 +/- 52%; HD patients: 251 +/- 55, 244 +/- 36, and 318 +/- 50%; P: = 0.002). N:-monomethyl-L-arginine (LMA 1:1 micromol/min; LMA 2:2; LMA 3:4), given to block baseline NO generation, showed an enhanced response in HD patients (control subjects: 90 +/- 2, 83 +/- 2, and 74 +/- 4%; HD patients: 84 +/- 3, 73 +/- 3, and 64 +/- 4%; P: = 0.037). Vascular response to three doses of norepinephrine (60, 120, and 240 pmol/min) was comparable in both groups, which indicated similar endothelium-independent vasoconstriction. In summary, in normotensive HD patients, (1) vasodilation to defined doses of exogenous NO was reduced, (2) there was no evidence of substrate deficiency of NOS, and (3) stimulation of NOS was impaired; however, (4) baseline NO generation was increased. It is concluded that in HD patients, the NO system has a reduced capacity to regulate vascular tone and this impairment is most significant under conditions of NOS stimulation.
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PMID:Evidence in vivo showing increase of baseline nitric oxide generation and impairment of endothelium-dependent vasodilation in normotensive patients on chronic hemodialysis. 1096 98

Asymmetric dimethylarginine (ADMA), a compound detectable in human plasma, is an endogenous inhibitor of NO synthase. Endothelial dysfunction is an early event in atherogenesis, and large-vessel atherosclerosis is a major cause of morbidity and mortality in patients with type 2 diabetes mellitus. Fifty patients with type 2 diabetes mellitus were studied at baseline and 5 hours after ingestion of a high-fat meal. Plasma ADMA measured by using high-performance liquid chromatography increased from 1.04+/-0.99 to 2.51+/-2.27 micromol/L (P:<0.0005). Brachial arterial vasodilation after reactive hyperemia, a NO-dependent function, measured by high-resolution ultrasound, decreased from 6.9+/-3.9% at baseline to 1.3+/-4.5% (P:<0.0001). These changes occurred in association with increased plasma levels of triglycerides and very low density lipoprotein triglycerides, with reduced low density lipoprotein cholesterol and high density lipoprotein cholesterol, and with no changes in total cholesterol. The increase in plasma ADMA in response to a high-fat meal was significantly and inversely related to the decrease in percent vasodilation. In 10 of the subjects studied with a similar protocol on another day, no significant changes in the brachial artery flow responses or in plasma ADMA were observed 5 hours after ingestion of a nonfat isocaloric meal. The data suggest that ADMA may contribute to abnormal blood flow responses and to atherogenesis in type 2 diabetics.
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PMID:Acute elevations of plasma asymmetric dimethylarginine and impaired endothelial function in response to a high-fat meal in patients with type 2 diabetes. 1097 46

Liposomes have been artificially made into membranous vesicles composed essentially of naturally occurring phospholipids and have been found to serve as a carrier of drugs and an immunological adjuvant. After being intravenously injected, they are quickly removed from the blood circulation and trapped by Kupffer cells of the liver and macrophages of spleen. However, the changes liposomes exert in these cells with which liposomes interact remain unresolved. To clarify this point is very important to assure the safe use of liposomes as drug carriers. Macrophages have many unique functions, and nitric oxide (NO) produced by NO synthase (NOS) which is induced in response to some cytokines and bacterial products such as lipopolysaccharide (LPS) is responsible for the bactericidal, tumoricidal and immune regulatory activities. On the other hand, overexpressed NO is implicated in the development of atherosclerosis, DNA injury, and hypotension associated with septic shock. This article focuses on the effects of liposomes on NO production from LPS-stimulated mice peritoneal macrophages in vitro; we found that liposomes composed of phosphatidylserine inhibit NO production. We also discuss the mechanism of the inhibitory activity of liposomes.
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PMID:Liposomes as immunomodulator--inhibitory effect of liposomes on NO production from macrophages. 1108 50

1. Mice lacking the apolipoprotein E and low density lipoprotein receptor genes (E degrees xLDLR degrees ) develop atherosclerosis and endothelial dysfunction. The aim of this study was to characterize the roles of L-arginine and tetrahydrobiopterin (BH(4)) for endothelium-dependent relaxation and the changes in the vasoconstrictor response to endothelin-1 (ET-1) in thoracic aortic rings of E degrees xLDLR degrees mice. 2. Histological examination revealed severe atherosclerosis of the thoracic aorta of E degrees xLDLR degrees mice. Relaxations induced by acetylcholine (Ach), but not that to sodium nitroprusside, were significantly impaired in E degrees xLDLR degrees mice compared to control mice indicating attenuated endothelium-dependent relaxations. 3. Preincubation with the nitric oxide (NO) substrate L-arginine did not affect, whereas the co-factor for NO synthase, BH(4), slightly improved the relaxations induced by Ach. Combined preincubation with L-arginine and BH(4) induced a pronounced enhancement of Ach-induced relaxations in E degrees xLDLR degrees mice. The relaxations induced by Ach in E degrees xLDLR degrees mice in the presence of L-arginine and BH(4) were not different from those observed in control mice. 4. Preincubation with superoxide dismutase did not affect Ach-induced relaxations in aorta from E degrees xLDLR degrees mice. 5. The contractile response to ET-1 was enhanced in E degrees xLDLR degrees mouse aorta. The contractions were abolished by the ET(A) receptor antagonist LU 135252. The ET(B) receptor agonist sarafotoxin 6c did not induce contractions or relaxations. 6. It is concluded that endothelial dysfunction of E degrees xLDLR degrees mouse aorta is reversed by combined administration of L-arginine and BH(4). In addition, the ET(A) receptor-mediated vasoconstriction by ET-1 is enhanced in E degrees xLDLR degrees mice.
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PMID:Endothelial dysfunction in atherosclerotic mice: improved relaxation by combined supplementation with L-arginine-tetrahydrobiopterin and enhanced vasoconstriction by endothelin. 1109 96

Nitric oxide (NO) production by inducible NO synthase (iNOS) may play an important role in the pathogenesis of atherosclerosis. Although fluvastatin has been shown to reduce progression of atherosclerosis, it is not known whether it regulates iNOS expression. We investigated the effects of fluvastatin on iNOS expression and subsequent NO synthesis in vascular smooth muscle cells (VSMCs) and the mechanism by which fluvastatin exerts its effects. Fluvastatin significantly increased interleukin-1ss (IL-1ss)-induced nitrite production by VSMCs in a time-dependent (0 to 24 hours) and dose-dependent (10(-)(8) to 10(-)(5) mol/L) manner. Increased nitrite production by fluvastatin was accompanied by increased iNOS mRNA and protein accumulation. IL-1ss induced nuclear factor-kappaB activation in VSMCs, which was not affected by fluvastatin. Exogenous mevalonate significantly prevented the stimulatory effect of fluvastatin on nitrite production. Cotreatment with geranylgeranyl-pyrophosphate also reversed the effect of fluvastatin. Furthermore, both Rho inhibitor C3 exoenzyme and Rho kinase inhibitor Y-27632 significantly increased IL-1ss-induced nitrite accumulation in VSMCs. These results demonstrated that fluvastatin upregulates iNOS expression and subsequent NO formation in rat VSMCs through inhibition of Rho.
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PMID:Fluvastatin upregulates inducible nitric oxide synthase expression in cytokine-stimulated vascular smooth muscle cells. 1111 1

Clotrimazole (CLT) is a drug known to interfere with cellular calcium homeostasis, which in turn is reported to intervene in cell proliferation and in the reactivity of small blood vessels. Experiments were designed to test the influence of CLT on the proliferative and vasorelaxant effect of bradykinin (BK) and on calcium homeostasis in smooth muscle cells (SMC). To this purpose two model systems were employed: (i) cultured human smooth muscle cells (HSMC), and (ii) isolated resistance arteries maintained in an organ bath. The effect of various concentrations of CLT (2-15 microM) on BK-induced proliferation of HSMC was quantitated by spectrometry following [3H]-thymidine incorporation, and intracellular calcium [Ca+]i was determined by spectrofluorimetry using Fura 2-AM assay. In other experiments the roles of BK receptor (AB2) and of thapsigargin were assessed. The reactivity of the resistance arteries was measured by the myograph technique, and the effects of BK, CLT, and NO synthase blocker, L-NAME were evaluated. The results showed that 10 microM CLT: (i) inhibits the BK-induced proliferation of HSMC by 45-50%: (ii) prevents the rise of [Ca2+]i induced by BK (120.8 +/- 12.4 nM vs. 235.8 +/- 34.1 nM), an cffect similar to that of "classic" L-type calcium channels blockers: (iii) reduces the release of Ca2+ entry induced by thapsigargin suggesting a possible inhibition of the capacitative Ca2+ entry. Organ bath assays showed that CLT enhanced the BK-induced relaxation of the resistance arteries by an endothelium NO-independent pathway. Together, these data suggest that the mechanism of action of CLT on SMC implies mainly a modification of intracellular calcium homeostasis, with a minor contribution of BK B2 receptors. These new distinctive features of CLT effects suggest the potential use of this drug in the therapy of cardiovascular diseases associated with SMC increased proliferation and impeded relaxation in small arteries, such as atherosclerosis and restenosis.
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PMID:Clotrimazole inhibits smooth muscle cell proliferation and has a vasodilator effect on resistance arteries. 1112 88

Since the demonstration of the obligatory role of the endothelium in arterial relaxation by Furchgott and Zawadzki (1980), there has been great interest in the role of the endothelium in vascular disease. Apart from endothelium-dependent vasodilation, other important functions of the endothelium have now been studied, that is, the regulation of adhesion and infiltration of leukocytes and inhibition of platelet adhesion and aggregation. Many functions of the endothelium are influenced by nitric oxide (NO), which is synthesized by endothelial NO synthase. Endothelial dysfunction in hypercholesterolemic patients is in large part due to a reduced bioavailability of NO. Multiple factors contribute to this, including increased inactivation of NO by radicals and inhibition of NO formation by different mechanisms. The functional implications of endothelial dysfunction are not completely defined. However, recent studies suggest that endothelial dysfunction contributes to myocardial perfusion abnormalities. Furthermore, endothelial dysfunction may play an important role with respect to development and progression of atherosclerosis because the endothelium is involved in the regulation of key events of the atherosclerotic process. Endothelial dysfunction in hypercholesterolemia is reversible by cholesterol-lowering treatment, that is treatment with HMG-CoA-reductase inhibitors. First experimental data suggest that maneuvers that increase the bioavailability of NO in hypercholesterolemia may even result in regression of preexisting atherosclerotic lesions.
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PMID:Endothelial dysfunction in hypercholesterolemia: mechanisms, pathophysiological importance, and therapeutic interventions. 1112 9


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