UMLS:C0004153 - FACTA Search

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

Current concepts for the explanation of endothelial dysfunction and accelerated atherosclerosis in uremia propose a reduced vascular bioavailability of nitric oxide (NO). The aim of the present study was to test the contributions of NO and NO/prostacyclin (PGI(2))-independent mechanisms to both baseline vascular tone and agonist-induced endothelium-dependent vasodilation in patients on hemodialysis (HD). In 10 HD patients and eight matched healthy control subjects, forearm blood flow (FBF) was measured at rest and during intrabrachial infusions of norepinephrine (NE; endothelium-independent vasoconstrictor, 60, 120, and 240 pmol/min) and N-monomethyl-L-arginine (blocker of NO synthases, 16 micromol/min). After inhibition of cyclo-oxygenase by ibuprofen (1200 mg orally), endothelium-dependent and -independent vasodilation was assessed by infusion of acetylcholine (ACh; 1, 5, 10, 50, 100, and 300 nmol/min) and sodium-nitroprusside (2.5, 5, and 10 microg/min). NO/PGI(2)-independent vasodilation was tested by equal infusions of ACh during NO clamp. N-monomethyl-L-arginine reduced resting FBF to a comparable degree in both groups. Vascular responses to ACh were reduced in HD (P = 0.003 versus control by ANOVA), whereas those to sodium nitroprusside were mainly at control level. Infusion of ACh during NO clamp caused a similar increment of FBF in both groups. NO-mediated vasodilation as calculated by the difference between ACh-induced responses without and with NO clamp was substantially impaired in HD (P < 0.001) compared with control. In HD patients, baseline NO-mediated arteriolar tone is at control level. This study provides first evidence that endothelial dysfunction of uremic patients as shown by reduced agonist-induced endothelium-dependent vasodilation is attributable to reduced stimulation of NO, whereas the NO/PGI(2)-resistant portion of ACh-mediated vasodilation is unaffected.
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PMID:Reduced agonist-induced endothelium-dependent vasodilation in uremia is attributable to an impairment of vascular nitric oxide. 1572 85

Impairment of endothelium-dependent vasodilation is associated with the initiation and development of atherosclerosis. Vasodilator prostanoids constitute a protective mechanism in maintaining normal vasomotor function. In the current study, we determined the effect of in vitro vitamin E supplementation at physiologically relevant concentrations (10-60 micromol/L) on the production of the vasodilator prostanoids prostaglandin I(2) (PGI(2); prostacyclin) and prostaglandin E(2)(PGE(2)) by human aortic endothelial cells (HAECs) as well as its underlying mechanism. Results showed that vitamin E dose dependently (10-40 micromol/L) increased the production of both prostanoids by HAECs. This was associated with a dose-dependent (10-40 micromol/L) upregulation of cytosolic phospholipase A(2) (cPLA(2)) expression and arachidonic acid release. In contrast, vitamin E dose dependently (10-60 micromol/L) inhibited cyclooxygenase (COX) activity but did not affect the expression of either COX-1 or COX-2, indicating that the effect of vitamin E on COX activity was post-translational. Thus, vitamin E had opposing effects on the 2 key enzymes in prostanoid biosynthesis; at the concentrations used in this study, this resulted in a net increase in the production of vasodilator prostanoids. The vitamin E-induced increase in PGI(2) and PGE(2) production may contribute to its suggested beneficial effect in preserving endothelial function.
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PMID:Vitamin E increases production of vasodilator prostanoids in human aortic endothelial cells through opposing effects on cyclooxygenase-2 and phospholipase A2. 1604 7

Coxibs, such as rofecoxib, celecoxib, and valdecoxib, selectively inhibit cyclooxygenase (COX)-2, the mainly inducible, pro-inflammatory COX isoform. Unlike traditional non-steroidal anti-inflammatory drugs (NSAIDs) most coxibs do not significantly inhibit COX-1 and are therefore less toxic to the gastrointestinal tract. Hence, coxibs widely replaced traditional NSAIDs for treatment of arthritis and other painful inflammatory conditions. In many, but not all, clinical studies, coxibs became associated with higher risks of myocardial infarction (MI) and stroke. Several mechanisms may be involved in the pathogenesis of such complications. First, selective inhibition of COX-1 lowers platelet synthesis of thromboxane (TXA(2)), a thrombogenic and atherogenic eicosanoid. Selective inhibition of COX-2 limits endothelial cell synthesis of prostacyclin (PGI(2)), an arachidonic acid product that opposes the effects of thromboxane. In apoE-/- mice, interruption of TXA(2) signaling by deletion of its receptor (TP) limits atherogenesis, whereas interruption of PGI2 signaling by deletion of its receptor (IP) accelerates atherogenesis. This suggests that selective inhibition of COX-2 can disrupt the physiological balance between thromboxane and prostacyclin and thus increase atherosclerosis, thrombogenesis, and the risk of cardiovascular complications. Second, COX inhibition can raise levels of arachidonic acid, which can inhibit mitochondrial oxidative phosphorylation (OXPHOS) and increase OXPHOS generation of reactive oxygen species. Several NSAIDs, including coxibs and meloxicam, directly uncouple or inhibit OXPHOS. Studies of apoE-/- mice indicate that mitochondrial dysfunction plays an early role in atherogenesis. Third, many NSAIDs exhibit COX-independent properties. For example, in animal models, short-term treatment with celecoxib reduces monocyte chemotaxis by reducing expression of monocyte chemoattractant protein (MCP)-1. However, long-term treatment results in the opposite effect and accelerates atherogenesis. In conclusion, to reduce the risk of cardiovascular complications during long-term coxib therapy, low-dose aspirin supplementation should be considered. An alternative is to use a less COX-2-selective inhibitor such as meloxicam. Genotyping of -765 alleles of the COX-2 gene promoter and examining the polymorphism of other genes involved in eicosanoid metabolism or NSAID degradation may become helpful in predicting patients who are at higher risk of cardiovascular complications during selective COX-2 inhibitor therapy.
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PMID:Cardiovascular complications of non-steroidal anti-inflammatory drugs. 1625 52

In humans, hypercholesterolemia and hypertriglyceridemia induce endothelial dysfunction and therefore lead to atherosclerosis. In contrast, rats are resistant to atherosclerosis. Here we analyze whether rats respond to hypercholesterolemia and hypertriglyceridemia by developing of endothelial dysfunction. To induce hypercholesterolemiaWistar-Kyoto (WKY) and spontaneous hypertensive (SHR) rats were fed for 12 weeks with AIN93 diet supplemented with cholesterol (1%) and butter (20%). To induce hypertriglyceridemiaWistar were fed for 8 weeks with AIN93 diet supplemented with 60% fructose. In all experimental groups nitric oxide (NO)-dependent and prostacyclin (PGI(2))-dependent function was assessed in the isolated aorta. Additionally in hypertriglyceridemic rats endothelial function in the isolated mesenteric resistance artery was analyzed. NO-dependent vasodilation induced by acetylcholine or histamine in aorta of SHR and WKY rats was modestly impaired. Hypercholesterolemic diet fed to WKY and SHR rats induced a rise in total cholesterol and low-density lipoproteins (LDL) cholesterol by 2.5 and 4.5 fold, respectively, but did not further impair NO-dependent vasodilation. Although basal production of PGI(2) in aortic rings from SHR rats was five fold higher than in aortic rings from WKY rats, the hypercholesterolemic diet did not further affect aortic PGI(2) production in either rat strain. Endothelium-independent vasodilation induced by SNAP remained also unchanged. On the other hand, the hypertriglyceridemic diet given to Wistar rats led to a selective 1.5-2 fold elevation of triglycerides that was associated with the impairment of NO-dependent relaxation in aorta as well as in the mesenteric resistance artery. Interestingly, the basal production PGI(2) by aortic rings was not modified by hypertriglyceridemic diet. Again endothelium-independent relaxation induced by S-nitroso-N-acetyl-penicilamine (SNAP) was not affected. In summary, although in humans both hypercholesterolemia and hypertriglyceridemia are associated with endothelial dysfunction, in rats hypertriglyceridemia only led to the impairment of NO-dependent vasodilation. Hypercholesterolemia did not modify endothelial function even in hypertensive rats that display pre-existing alterations in vasodilator function.
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PMID:Hypertriglyceridemia but not hypercholesterolemia induces endothelial dysfunction in the rat. 1641 93

This study was designed to test the hypothesis that fenofibrate, the peroxisome proliferator-activated receptor alpha (PPARalpha) activator, improves age-related endothelial dysfunction in small mesenteric arteries (SMA). Adult and aged rats were treated with fenofibrate and then endothelium-dependent relaxations of SMA; expressions of endothelial NO synthase (eNOS), cyclo-oxygenase (COX-1 and COX-2) and superoxide dismutases (SOD) (Cu/Zn SOD, Mn SOD and EC SOD) proteins and release of TXB(2) and 6-keto-PGF(1alpha) were assessed. Fenofibrate improved endothelium-dependent vasodilatation of arteries from old rats and decreased participation of endothelial vasoconstrictor products, sensitive to COX-1 and COX-2 inhibitors and acting on Tp receptor. Fenofibrate decreased expressions of COX-1 and COX-2, and generation of TXA(2). Release of vasodilator PGI(2) and U46619-induced contraction remained unaltered. Neither NO-mediated vasodilatation nor eNOS expression was affected. The addition of the scavengers, SOD and catalase increased relaxation only in SMA from control rats. Finally, fenofibrate did not change expressions of Cu/Zn SOD and Mn SOD but it increased EC SOD towards that observed in arteries from adult rats. Fenofibrate improves endothelial function in resistance arteries from aged rats by decreasing expression of COX-1 and COX-2 together with enhancing anti-oxidant capacity of the vessel wall probably through the increased expression of EC SOD. This study provides evidence that PPARalpha may have clinical applications toward maintaining endothelial function during ageing.
Atherosclerosis 2007 Jul
PMID:Fenofibrate improves age-related endothelial dysfunction in rat resistance arteries. 1697 46

Atherosclerotic plaque formation is a dynamic process involving repeated injury and inflammation of the endothelium. We have demonstrated previously that thrombin and tryptase stimulation of human coronary artery endothelial cells (HCAEC) leads to increased phospholipase A(2) (PLA(2)) activity and generation of membrane phospholipid derived inflammatory metabolites, including eicosanoids and platelet activating factor. Thus, our hypothesis is that selective PLA(2) inhibitors have therapeutic potential as anti-inflammatory agents. Stimulation of confluent HCAEC monolayers with thrombin or tryptase resulted in a concentration and time-dependent increase in both prostaglandin E(2) (PGE(2)) and prostacyclin (PGI(2)) production. Pretreatment with PX-18 to inhibit secretory PLA(2) or BEL to inhibit calcium-independent PLA(2) prior to thrombin or tryptase stimulation resulted in a significant inhibition of both PGI(2) and PGE(2) release. However, pretreatment with methyl arachidonyl fluorophosphonate (MAFP), a widely used inhibitor of cytosolic PLA(2) isoforms, resulted in a significant potentiation of both thrombin and tryptase stimulated PGI(2) and PGE(2) release as a consequence of increased free arachidonic acid production. We conclude that the use of selective PLA(2) inhibitors may be of therapeutic benefit in the development and progression of atherosclerosis, however, the development of such an agent requires rigorous screening.
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PMID:Prostaglandin production in human coronary artery endothelial cells is modulated differentially by selective phospholipase A(2) inhibitors. 1737 79

Atherosclerosis, the underlying cause of cardiovascular disease, is characterized by lipid accumulation, lipoprotein oxidation, and inflammation. Products of the cyclooxygenase (COX) pathway participate in acute and chronic inflammation. The inducible form of COX, COX-2, generates lipid mediators of inflammation that are pro-inflammatory and COX-2-selective inhibitors are potent anti-inflammatory agents. However, clinical data suggest an increased risk of cardiovascular side effects in patients using COX-2-selective inhibitors. In this paper, we sought to determine the effect of COX-2 deficiency on atherosclerosis-related lipoprotein metabolism in mice. We demonstrate that COX-2 deficiency resulted in (i) accumulation of lipids in circulation and liver, (ii) pro-inflammatory properties of HDL as measured by HDL's increased reactive oxygen species (ROS) content, decreased paraoxonase 1 (PON1) activity, decreased serum apoA-1, reduced ability to efflux cholesterol and to prevent LDL oxidizability, and (iii) increased TXB(2) in circulation. Moreover, when placed on an atherogenic diet, COX-2 deficiency resulted in (i) increased lipid deposition in the aorta, (ii) a further dramatic imbalance in circulating eicosanoids, i.e. decreased serum PGI(2) coupled with increased PGE(2) and TXB(2), and (iii) a marked elevation of pro-inflammatory cytokines, TNF and IL-6. Our results suggest, for the first time, that COX-2 deficiency contributes to the pro-atherogenic properties of HDL in mice.
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PMID:A novel anti-atherogenic role for COX-2--potential mechanism for the cardiovascular side effects of COX-2 inhibitors. 1764 85

Prostacyclin (PGI(2)) is a major product of COX-2 catalyzed metabolism of arachidonic acid in the endothelium. Recent studies have demonstrated that PGI(2) protects against atherothrombosis. The prostacyclin receptor knockout mice exhibit increased atherosclerosis, enhanced thrombosis, and enhanced proliferative response to carotid vascular injury with increased intima to media ratios [1-3]. Moreover, the recent withdrawal of rofecoxib (Vioxx) due to increased cardiovascular events further supports the critical role of prostacyclin in inhibiting atherothrombosis in humans. Such studies have paralleled intense chemical biology studies to develop more stable prostacyclin analogues. Indeed a number of these analogues are currently being successfully used for the treatment of pulmonary hypertension. In this review we will summarize the current literature on some principles of prostacyclin analogue development, our current understanding of the receptor, and recent developments which implicate prostacyclin in atherothrombotic protection. More than 68 million Americans suffer from cardiovascular disease, which causes more deaths, disability and economic loss than any other group of diseases. Further clinical investigations of orally stable prostacyclin analogues for treatment of cardiovascular diseases other than pulmonary hypertension may now be warranted.
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PMID:Prostacyclin, atherothrombosis, and cardiovascular disease. 1769 54

Prostanoids are cyclic lipid mediators which arise from enzymic cyclooxygenation of linear polyunsaturated fatty acids, e.g. arachidonic acid (20:4 n 6, AA). Biologically active prostanoids deriving from AA include stable prostaglandins (PGs), e.g. PGE(2), PGF(2alpha), PGD(2), PGJ(2) as well as labile prostanoids, i.e. PG endoperoxides (PGG(2), PGH(2)), thromboxane A(2) (TXA(2)) and prostacyclin (PGI(2)). A "Rabbit aorta Contracting Substance" (RCS) played important role in discovering of labile PGs. RCS was discovered in the Vane's Cascade as a labile product released along with PGs from the activated lung or spleen. RCS was identified as a mixture of PG endoperoxides and thromboxane A(2). Stable PGs regulate the cell cycle, smooth muscle tone and various secretory functions; they also modulate inflammatory and immune reactions. PG endoperoxides are intermediates in biosynthesis of all prostanoids. Thromboxane A(2) (TXA(2)) is the most labile prostanoid (with a half life of 30 s at 37 degrees C). It is generated mainly by blood platelets. TXA(2) is endowed with powerful vasoconstrictor, cytotoxic and thrombogenic properties. Again the Vane's Cascade was behind the discovery of prostacyclin (PGI(2)) with a half life of 4 min at 37 degrees C. It is produced by the vascular wall (predominantly by the endothelium) and it acts as a physiological antagonist of TXA(2). Moreover, prostacyclin per se is a powerful cytoprotective agent that exerts its action through activation of adenylate cyclase, followed by an intracellular accumulation of cyclic-AMP in various types of cells. In that respect PGI(2) collaborates with the system consisting of NO synthase (eNOS)/nitric oxide free radical (NO)/guanylate cyclase/cyclic-GMP. Both cyclic nucleotides (c-AMP and c-GMP) act in synergy as two energetic fists which defend the cellular machinery from being destroyed by endogenous or exogenous aggressors. Recently, a new partner has been recognized in this endogenous defensive squadron, i.e. a system consisting of heme oxygenase (HO-1)/carbon monoxide (CO)/biliverdin/biliverdin reductase/bilirubin. The expanding knowledge on the pharmacological steering of this enzymic triad (PGI(2)-S/eNOS/HO-1) is likely to contribute to the rational therapy of many systemic diseases such as atherosclerosis, diabetes mellitus, arterial hypertension or Alzheimer diseases. The discovery of prostacyclin broadened our pathophysiological horizon, and by itself opened new therapeutic possibilities. Prostacyclin sodium salt and its synthetic stable analogues (iloprost, beraprost, treprostinil, epoprostenol, cicaprost) are useful drugs for the treatment of the advanced critical limb ischemia, e.g. in the course of Buerger's disease, and also for the treatment of pulmonary artery hypertension (PAH). In this last case a synergism between prostacyclin analogues and sildenafil (a selective phosphodiesterase 5 inhibitor) or bosentan (an endothelin ET-1 receptor antagonist) points our to complex mechanisms controlling pulmonary circulation. At the Jagiellonian University we have demonstrated that several well recognised cardiovascular drugs, e.g. ACE inhibitors (ACE-I), statins, some of beta-adrenergic receptor antagonists, e.g. carvedilol or nebivolol, anti-platelet thienopyridines (ticlopidine, clopidogrel) and a metabolite of vitamin PP--N(1)-methyl-nicotinamide--all of them are endowed with the in vivo PGI(2)-releasing properties. In this way, the foundations for the Endothelial Pharmacology were laid.
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PMID:Prostacyclin among prostanoids. 1827 80

The effects of changes in flow velocity waveform and arterial geometry before and after percutaneous coronary intervention (PCI) in the right coronary artery (RCA) were investigated using computational fluid dynamics. An RCA from a patient with a stenosis was reconstructed based on multislice computerized tomography images. A nonstenosed model, simulating the same RCA after PCI, was also constructed. The blood flows in the RCA models were simulated using pulsatile flow waveforms acquired with an intravascular ultrasound-Doppler probe in the RCA of a patient undergoing PCI. It was found that differences in the waveforms before and after PCI did not affect the time-averaged wall shear stress and oscillatory shear index, but the phase angle between pressure and wall shear stress on the endothelium, stress phase angle (SPA), differed markedly. The median SPA was -63.9 degrees (range, -204 degrees to -10.0 degrees ) for the pre-PCI state, whereas it was 10.4 degrees (range, -71.1 degrees to 25.4 degrees ) in the post-PCI state, i.e., more asynchronous in the pre-PCI state. SPA has been reported to influence the secretion of vasoactive molecules (e.g., nitric oxide, PGI(2), and endothelin-1), and asynchronous SPA ( approximately -180 degrees ) is proposed to be proatherogenic. Our results suggest that differences in the pulsatile flow waveform may have an important influence on atherogenesis, although associated with only minor changes in the time-averaged wall shear stress and oscillatory shear index. SPA may be a useful indicator in predicting sites prone to atherosclerosis.
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PMID:Stress phase angle depicts differences in coronary artery hemodynamics due to changes in flow and geometry after percutaneous coronary intervention. 1915 Dec 51

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