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)

Isoprostanes (IPs) are indicators of in-vivo oxidative stress, and have been successfully used as markers for chronic inflammatory processes. The presence of chronic periodontal disease and cigarette smoking has been individually linked to the development of atherosclerosis, yet data regarding oxidative stress in this context are not available yet. The aim of this study was to evaluate levels of the salivary prostaglandins (PGs) 8-epi-PGF(2alpha), 6-oxo-PGF(1alpha), thromboxane B(2) (TXB(2)) and PGF(2alpha) in association with periodontal disease status with and without additional cigarette smoking. We analyzed saliva samples from 121 adults, (aged 21-73 years, 90 non-smokers, 31 smokers) for levels of 8-epi-PGF(2alpha), 6-oxo-PGF(1alpha), TXB(2) and PGF(2alpha). On the basis of periodontal disease indices the periodontal status of each subject was assessed and outcomes were then correlated with smoking status and laboratory findings. Salivary 8-epi-PGF(2alpha) levels increased with deteriorating plaque index, and were significantly higher (115.5 +/- 23.5 pg/ml) in smoking individuals, when compared to non-smokers (70.2 +/- 20.4 pg/ml, p<0.0001). In addition, smokers showed higher TXB(2) and PGF(2alphas) and lower 6-oxo-PGF(1alpha) levels p<0.0001). Oxidative stress, as reflected by elevated salivary 8-epi-PGF(2alpha) levels, is associated with the extent of periodontal disease and is significantly aggravated by concomitant tobacco abuse. Chronic inflammation and smoking have been individually associated with the development of atherosclerosis. The results of this study indicate that: 1) salivary IPs can reliably assess the degree of oxidative stress, and: 2) smoking and periodontal disease are two modifiable cardiovascular risk factors, able to potentiate each other.
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PMID:Salivary isoprostanes indicate increased oxidation injury in periodontitis with additional tobacco abuse. 1726 90

Increased lipid peroxidation has been identified as a key mechanism for the development of atherosclerosis and inflammatory vascular damage. Determination of plasma concentration and urinary excretion of some F(2)-isoprostanes (by immunometric assays or by mass-spectrometry), has been demonstrated to be a reliable approach to the assessment of lipid peroxidation, and therefore of oxidative stress in vivo . Several lines of evidence suggest that isoprostane generation may reflect oxidative stress in experimental and human atherosclerosis. Increased lipid peroxidation may precede the development of atherosclerosis. In fact, urinary excretion or plasma levels of an abundantly generated F(2)-isoprostane, 8-iso-PGF(2alpha) have been found to be more elevated in subject with cardiovascular risk factors than in healthy subjects. Some isoprostanes, in particular 8-iso-PGF(2alpha) have been demonstrated to have biological activities that may contribute to the progression of vascular damage inducing endothelial and platelet activation and being powerful vasocostrictors. Increased lipid proxidation may be implicated in the bioactivity of angiotensin II. Experimental data indicate that increased oxidative stress due to activation of NAD(P)H oxidase is an obligatory step in its pro-hypertensive and pro-atherosclerotic effects. Increased generation of F(2)-isoprostanes is observed in clinical and experimental conditions in which angiotensin II activity is increased. In conclusion, measurement of some F(2)-isoprostanes in biological liquids represents a reliable marker of oxidative stress in vivo. The potential contribution of these compounds to the pathophysiology of the vascular damage and atherosclerosis has not yet been defined.
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PMID:Lipid peroxidation, isoprostanes and vascular damage. 1733 73

Thromboxane A(2) (TXA(2)) and 8-iso-PGF(2alpha) are two prostanoid agonists of the thromboxane A(2) receptor (TP), whose activation has been involved in platelet aggregation and atherosclerosis. Agents able to counteract the actions of these agonists are of great interest in the treatment and prevention of cardiovascular events. Here, we investigated in vitro and in vivo the pharmacological profile of BM-520, a new TP antagonist. In our experiments, this compound showed a great binding affinity for human washed platelets TP receptors, and prevented human platelet activation and aggregation induced by U-46619, arachidonic acid and 8-iso-PGF(2alpha). The TP receptor antagonist property of BM-520 was confirmed by its relaxing effect on rat aorta smooth muscle preparations precontracted with U-46619 and 8-iso-PGF(2alpha). Further, its TP antagonism was also demonstrated in vivo in guinea pig after a single intravenous injection (10 mg kg(-1)). We conclude that this novel TP antagonist could be a promising therapeutic tool in pathologies such as atherosclerosis where an increased production of TXA(2) and 8-iso-PGF(2alpha), as well as TP activation are well-established pathogenic events.
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PMID:BM-520, an original TXA2 modulator, inhibits the action of thromboxane A2 and 8-iso-prostaglandin F2alphain vitro and in vivo on human and rodent platelets, and aortic vascular smooth muscles from rodents. 1764 84

Obesity in children appears to be associated with increased risk of cardiovascular and metabolic diseases later in life. Early development of insulin resistance and impaired oxidant-antioxidant status may lead to endothelial dysfunction and increased carotid intima media thickness (IMT) even in childhood. The aim of this study was to measure IMT and the relationship between IMT, insulin resistance and oxidant status in obese pre-pubertal children. In 53 obese pre-pubertal children (27M/26F, mean age 8+/-2 years), anthropometric measurements and inflammatory markers (hs-CRP and PGF-2 alpha), were evaluated compared with 41 healthy pre-pubertal subjects (21M/20F, mean age 7+/-2 years). OGTT was performed and insulin resistance (IR) indices (HOMA-IR, WBISI, G/I and QUICKI) were calculated in all patients. High-resolution ultrasound techniques were used to evaluate IMT. Obese children had higher levels of PGF-2 alpha and hs-CRP compared to healthy subjects (p=0.001 and p=0.005). Furthermore, fasting insulin levels and HOMA-IR were higher in obese children than in controls (p=0.001 and p=0.001) while WBISI was significantly lower (p=0.002). In addition, obeses had an increased IMT (p=0.001). In obese children there was a significant correlation between IMT and indices of IR (HOMA-IR: beta=-1.233, p=0.002; WBISI: beta=-0.921, p=0.008; G/I: beta=-0.811, p=0.003) and between IMT and PGF-2 alpha (beta=0.505, p=0.004). After categorizing subjects according to tertiles of body mass index (BMI) (<or=21.42, 21.42-26.23 and >or=26.23 kg/m(2)) and to waist circumference (WC) (<or=68.28, 68.28-79.04 and >or=79.04 cm), no influence of BMI or WC on IMT were found in the three groups. In conclusion, early changes in glucose metabolism and an alteration of oxidant-antioxidant status may be present in obese pre-pubertal children; this could lead to increase IMT and early cardiovascular disease.
Atherosclerosis 2008 Mar
PMID:Obese related effects of inflammatory markers and insulin resistance on increased carotid intima media thickness in pre-pubertal children. 1834 44

The receptor for advanced glycation endproducts (RAGE) is overexpressed at sites of vascular pathology. A soluble RAGE isoform (sRAGE) neutralizes the ligand-mediated damage by acting as a decoy. We hypothesized that in hypercholesterolemia up-regulation of the ligand-RAGE axis may bridge impairment of nitric oxide biosynthesis with oxidative stress. We measured in 60 hypercholesterolemic patients and 20 controls plasma total sRAGE levels, urinary 8-iso-prostaglandin (PG) F(2alpha) excretion, and plasma levels of asymmetric dimethylarginine (ADMA). The effects of two structurally different statins (pravastatin and atorvastatin) on these parameters were analyzed in 20 hypercholesterolemic subjects free of vascular disease. Plasma sRAGE was significantly lower, ADMA and urinary 8-iso-PGF(2alpha) were higher, in hypercholesterolemic versus normocholesterolemic patients. Patients on statin treatment with previous myocardial infarction had lower 8-iso-PGF(2alpha), higher sRAGE, and unchanged ADMA levels compared to subjects free of vascular disease. On multivariate regression analysis only 8-iso-PGF(2alpha) and ADMA predicted sRAGE levels. An 8-week treatment with either statin was associated with a significant reduction in urinary 8-iso-PGF(2alpha), whereas only atorvastatin raised sRAGE levels near to normal values, with no change in ADMA levels. sRAGE might serve as an endogenous protecting factor for accelerated atherosclerosis mediated by oxidative stress and endothelial dysfunction in hypercholesterolemia.
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PMID:Decreased plasma soluble RAGE in patients with hypercholesterolemia: effects of statins. 1789 35

Early manifestations of kidney disease occur in atherosclerosis and activation of TP (thromboxane A(2)) receptors is implicated in atherosclerotic, diabetes, and renal diseases. The purpose of the present study was to analyze, in isolated, perfused mouse kidneys, the participation of TP receptors in renal vasoconstrictions and vasodilatations. In kidneys, taken from wild-type C57BL6, apolipoprotein E-deficient (ApoE-KO) and diabetic ApoE-KO mice, changes in perfusion pressure were recorded. Constrictions to TP receptor ligands U 46619, arachidonic acid, PGH(2), and 8-iso-PGF(2alpha), but not those to angiotensin II, endothelin, or norepinephrine, were inhibited by the selective TP receptor antagonist Triplion (S 18886; 10 nM). Acetylcholine and prostacyclin evoked biphasic responses during methoxamine constrictions; the constrictor part was blocked by Triplion. In ApoE-KO mouse kidneys, compared with C57BL6, a specific decrease in norepinephrine response and no modification in dilator responses were observed. In diabetic ApoE-KO mouse kidneys, constrictions to U 46619 and those to 8-iso-PGF(2alpha) were significantly and selectively augmented, without modification in the expression of the TP receptor, and again without any significant change in vasodilator activity. Thus TP receptors are functional, and their activation is not involved in norepinephrine, endothelin, and angiotensin II vasoconstrictions but is implicated in the unusual vasoconstrictions to acetylcholine and prostacyclin. Increased responsiveness of TP receptors occurs in diabetic ApoE-KO mouse kidneys. Thus early changes in TP receptor-mediated vasoconstrictor activity may participate in the development of kidney disease in atherosclerosis and diabetes.
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PMID:Altered TP receptor function in isolated, perfused kidneys of nondiabetic and diabetic ApoE-deficient mice. 1794 72

The 5-lipoxygenase (5-LO) pathway generates lipid mediators, i.e. the cysteinyl leukotrienes (cysLTs) LTC(4)/LTD(4) and LTB(4). CysLT receptors are expressed in endothelial cells (EC) and EC cysLT(2)-R activation induces diverse pro-inflammatory genes in vitro. We now report that LTD(4) promotes formation of an atherosclerosis-protective and anti-thrombotic eicosanoid by markedly up-regulating EC cyclooxygenase-2 (COX-2). CysLT-induced COX-2 transcripts were transiently up-regulated as determined by microarray and QRT-PCR analyses though COX-2 protein remained elevated for several hours. Prostacyclin formation, measured as its stable metabolite 6-keto-PGF(1alpha), was increased several fold in LTD(4)-stimulated ECs, and was inhibited by the COX-2-specific inhibitor, NS-398. COX-2 up-regulation was Ca(2+)-dependent and was partially blocked by cyclosporin A indicating that the 5-LO/COX-2 cross-talk involved signaling through a nuclear factor of activated T cells (NFAT) dependent pathway. Since prostacyclin is a major blood vessel-protective and anti-thrombotic eicosanoid, the EC cysLT(2)-R may limit its otherwise pro-inflammatory actions through a protective Ca(2+)/calcineurin/NFAT-dependent COX-2 feedback loop.
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PMID:5-Lipoxygenase/cyclooxygenase-2 cross-talk through cysteinyl leukotriene receptor 2 in endothelial cells. 1799 13

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

An increased synthesis of thromboxane (TX) A(2) is associated with a number of cardiovascular diseases including atherosclerosis, unstable angina and hypertension. We previously identified a subgroup of NZW rabbits in which isolated arteries failed to contract to the TX agonists, U46619 or I-BOP. In vascular smooth muscle membranes, there was a significant decrease in TX receptors, termed TP. These rabbits are referred to as vTP- and those with the TP receptor are called vTP+. Because TP receptors are expressed in some types of endothelial cells, the present study was designed to determine whether functional TP receptors are present in endothelial cells cultured from aortas of vTP+ and vTP- rabbits. Radioligand binding studies were performed with (125)I-BOP. Aortic endothelial cells from vTP+ rabbits exhibited specific and saturable binding. In contrast, in endothelial preparations from vTP- rabbit aortas, no measurable binding to (125)I-BOP was detected. Using an anti-TP receptor antibody, we compared the amount of receptor expressed in endothelial cell lysates obtained from vTP+ and vTP- rabbits. Consistent with the results observed radioligand binding assays, the expression of TP receptor protein was decreased in vTP- compared to vTP+ endothelial cells. An in vitro wound healing assay was used on confluent monolayers of endothelial cells. In the untreated vTP+ cells, the area of the scratch was completely closed by 30 h. In the vTP+ cells treated with U46619 (3 microM), the rate of closure of the scratch area was reduced with approximately 12% of the scratch area remaining at 30 h. Pretreatment with the TP receptor antagonist, SQ 29548 (10 microM) prevented the inhibitory effect of U46619. The rate of closure of the scratch in the vTP- was not altered by U46619. In a separate study, U46619 (3 microM) increased the release of 6-keto PGF(1alpha), the stable metabolite of prostacyclin, in vTP+ but not vTP- endothelial cells. Pretreatment with SQ29548 (10 microM) or the cyclooxygenase inhibitor, indomethacin (10 microM) blocked the increase in vTP+ endothelial cells. In vascular reactivity studies in aortas from vTP+ rabbits, removal of the endothelium enhanced the vasoconstrictor response to U46619 indicating that activation of endothelial TP receptors may modulate vascular tone via the release of the vasodilator, prostacyclin. The results of this study suggest an important role for endothelial TP receptors in modulating vascular function.
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PMID:Characterization of endothelial thromboxane receptors in rabbit aorta. 1881 32

A growing body of evidence suggests HIV patients are at a greater risk for developing atherosclerosis. However, clinical investigations have generated conflicting results with regard to whether antiretrovirals are independently involved in the development of HIV-associated atherosclerosis. By administering antiretrovirals in an atherogenic mouse model, we determined whether two commonly prescribed antiretrovirals, the protease inhibitor indinavir and the nucleoside reverse transcriptase inhibitor AZT, can induce premature atherosclerosis. C57BL/6 mice were administered an atherogenic diet+/-AZT, indinavir, or AZT plus indinavir for 20 weeks. Aortic intima-media thickness (IMT) and cross-sectional area (CSA) were determined. Compared to controls, treatment with AZT, indinavir or AZT plus indinavir, significantly increased aortic IMT and CSA. This suggests that antiretrovirals can directly exacerbate atherogenesis, in the absence of interaction with a retroviral infection. To elucidate the role of oxidant injury in the drug-induced initiation of atherosclerosis, a separate group of mice were treated for 2 weeks with an atherogenic diet+/-AZT, indinavir or AZT plus indinavir. Aortic reactive oxygen species (ROS) production and glutathione/glutathione disulfide (GSH/GSSG) ratios, as well as plasma levels of 8-isoprostanes (8-iso-PGF(2alpha)) and lipids were determined. At 2 weeks, aortic ROS was increased and GSH/GSSG ratios were decreased in all antiretroviral treatment groups. Plasma 8-iso-PGF(2alpha) was increased in the AZT and AZT plus indinavir-treated groups. At 20 weeks, increased ROS production was maintained for the AZT and indinavir treatment groups, and increased 8-iso-PGF(2alpha) levels remained elevated in the AZT treatment group. Cholesterol levels were moderately elevated in the AZT and AZT plus indinavir-treated groups at 2 but not 20 weeks. Conversely, indinavir treatment increased plasma cholesterol at 20 but not 2 weeks. Thus, though effects on plasma lipid levels occurred, with effects of the individual antiretrovirals variable across the treatment period, there was consistent evidence of oxidant injury across both early and late time points. Together with the known metabolic abnormalities induced by antiretrovirals, drug-induced oxidant production may contribute to the development of antiretroviral-associated atherosclerosis.
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PMID:HIV-1 antiretrovirals induce oxidant injury and increase intima-media thickness in an atherogenic mouse model. 1942 60


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