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)

Minor components of virgin olive oil (VOO) may play a key role in the beneficial effects of VOO on atherosclerosis. In the present study we evaluated the influence of the unsaponifiable fraction of VOO on the production of eicosanoids and nitric oxide (NO) by endothelial cells (HUVECs). Triglyceride-rich lipoprotein (TRLs) were isolated from human serum after the intake of meals enriched in 3 high-oleic acid oils, i.e., high-oleic sunflower (HOSO), VOO, or enriched-virgin olive (EVO) oils, the last-mentioned containing 2.4% of unsaponifiable matter. HOSO induced a greater accumulation of triglycerides (TGs) in the postprandial serum than VOO or EVO, as measured by calculating the area under the curve. The incubation with TRLs increased NO release by endothelial cells compared with untreated control cells, but the effects of the various TRLs did not differ. EVO-derived TRLs reduced the production of prostaglandin E(2) (PGE(2)) and thromboxane B(2) (TxB(2)) (the stable metabolite of TxA(2)) compared with VOO- or HOSO-derived TRLs. The release of PGI(2) (as 6-keto PGF(1alpha)) was similarly diminished by all TRLs compared with the control. In conclusion, the unsaponifiable fraction of VOO does not affect postprandial triglyceridemia, but it has favorable effects on endothelial function, mainly by reducing proinflammatory and vasoconstrictor eicosanoid synthesis (PGE(2) and TxB(2)).
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PMID:The unsaponifiable fraction of virgin olive oil in chylomicrons from men improves the balance between vasoprotective and prothrombotic factors released by endothelial cells. 1557 26

The production of peroxynitrite (ONOO(-)) in the endothelium decreases NO bioavailability, decreases vasorelaxation and changes vascular tone. ONOO(-) can also influence the production of prostacyclin-another vasorelaxant. We used a nanotechnological approach (nanosensors) to elucidate the release of NO, O(2)(-), and ONOO(-) in endothelium and their effect on production of prostanoids. The basal ONOO(-) concentration near the endothelium (3-5 microm) varied from 1 to 50 nmol/L and maximal calcium ionophore stimulated ONOO(-), did not exceed 900 nmol/L. The highest ONOO(-) concentrations were produced in ischemia/reperfusion atherosclerosis, diabetes, aging and vary among different racial groups (higher in Blacks than in Whites). ONOO(-) decreased PGI(2) activity with IC(50) approximately 150 nmol/L for 8 min reaction time, but has no effect of short reaction time. Prostaglandin E(1) decreased NO, O(2)(-), and ONOO(-) by limiting Ca(2+) flux into endothelium, decreased edema and vasoconstriction during ischemia/reperfusion. In endothelium (HUVEC's) of Black's the ONOO(-) concentrations were high 750+/-50 nmol/L while the lowest concentrations of vasorelaxants were 275+/-25 nmol/L of NO, 150+/-15 pb/100 microg protein of 6-keto-PGF(1)(alpha) as compared to White's (420+/-30 and 470+/- nmol/L for ONOO(-) and NO respectively and 280+/-20 pg/100 mg protein for 6-keto-PGF(1)(alpha)).
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PMID:Role of peroxynitrite in the process of vascular tone regulation by nitric oxide and prostanoids--a nanotechnological approach. 1562 93

The underlying mechanisms by which smoking induces cardiovascular diseases are largely unknown. The effect of smoking status on the cyclooxygenase (COX)-mediated inflammatory indicator prostaglandin F(2alpha) (PGF(2alpha)) has never been studied. Associations of cytokines and antioxidants and smoking status, have shown conflicting results. Urinary 15-keto-dihydro-PGF(2alpha) (a major metabolite of PGF(2alpha)), serum interleukin-6 (IL-6) and high sensitivity C-reactive protein (hsCRP), serum amyloid protein A (SAA), urinary 8-iso-PGF(2alpha) (an F(2)-isoprostane, indicator of oxidative stress), and serum alpha-tocopherol were quantified in a population-based sample (n = 642) of 77-year old men without diabetes. Fifty-five men were current smokers and 391 former smokers. Inflammatory indicators were increased in current smokers (15-keto-dihydro-PGF(2alpha), P < 0.001; IL-6, P = 0.01) than non-smokers. 8-iso-PGF(2alpha) was increased (P < 0.01) and alpha-tocopherol reduced (P < 0.001) in current smokers. Further, former smokers had increased formation of 15-keto-dihydro-PGF(2alpha), IL-6 and 8-iso-PGF(2alpha) compared non-smokers. This is the first study to show that smokers have increased PGF(2alpha) formation, thus enhanced COX-mediated inflammation, in addition to elevated levels of cytokines and isoprostanes. Subclinical COX- and cytokine-mediated inflammation and oxidative stress are ongoing processes not only in active smokers but also in former smokers which may contribute to the accelerated atherosclerosis associated with smoking.
Atherosclerosis 2005 Jul
PMID:Active smoking and a history of smoking are associated with enhanced prostaglandin F(2alpha), interleukin-6 and F2-isoprostane formation in elderly men. 1593 73

Oxidative stress may play a role in the development of atherosclerosis. The purpose of the present study was to explore the relationship between 8-isoprostaglandin F(2alpha) (8-iso-PGF(2alpha)) levels and the presence of coronary artery disease (CAD) and to also clarify whether 8-iso-PGF(2alpha) might add independently to measures of CAD extent. The study group consisted of 241 consecutive patients who were undergoing coronary angiography for suspected CAD. 8-iso-PGF(2alpha) levels were recorded for all participants. The analysis revealed a significant difference in 8-iso-PGF(2alpha) levels in patients with and without hypertension (P<0.001), in patients with diabetes relative to nondiabetic patients (P<0.05), and in males respect to females (P<0.001). A significant positive correlation was found between age and 8-iso-PGF(2alpha) levels (P<0.001). 8-iso-PGF(2alpha) levels correlated with the number of cardiovascular risk factors (P<0.001). 8-iso-PGF(2alpha) levels were higher in the CAD(+) respect to the CAD(-) groups (337.7+/-80.2 and 263.8+/-74.2 pg/ml and P<0.001). A stepwise elevation in the 8-iso-PGF(2alpha) levels was found depending on the number of affected vessels (P<0.001). The 8-iso-PGF(2alpha) levels showed a significant positive correlation with the numbers of >50 and >25% stenotic segments (P<0.001) and the extent score of coronary stenosis (P<0.001). The multivariate logistic regression analysis indicated 8-iso-PGF(2alpha) as an independent factor associated with CAD (odds ratio, 2.47 and P=0.001). The results suggested that 8-iso-PGF(2alpha) is associated with the presence of CAD in patients undergoing coronary angiography and is also related to the extent of coronary stenosis in Chinese population.
Atherosclerosis 2006 Feb
PMID:Associations of plasma 8-isoprostane levels with the presence and extent of coronary stenosis in patients with coronary artery disease. 1599 71

Several lines of evidence suggest that reactive oxygen species play a role in the development of vasculopathies, including those that define atherosclerosis, hypertension and restenosis after angioplasty. Confused picture emerging from prospective clinical trials of anti-oxidants may reflect inadequacy of traditional indices of lipid peroxidation in the recruitment of appropriate patients and in guiding the selection of the appropriate dose of anti-oxidant to be tested. Ex vivo indices of oxidant stress could have questionable veracity in assessing the actual rate of lipid peroxidation in vivo. The measurement of F(2)-isoprostanes (F(2)-iPs), formed non-enzimatically through free radical catalysed attack on esterified arachidonate, provides a reliable tool for identifying populations with enhanced rates of lipid peroxidation. Enhanced formation of F(2)-iPs, together with increased in vivo platelet activation, has been reported in association with several cardiovascular risk factors. Thus, it has been suggested that F(2)-iPs may transduce oxidant stress-dependent platelet activation. Measurements of 8-iso-PGF(2alpha), an abundant F(2)-iP formed in vivo, in urine may provide sensitive biochemical end-points for the assessment of the oxidant status of the patient and the true efficacy of anti-oxidant therapies. The incorporation of such biochemical end-points in clinical trials may help to verify the reliability of the oxidative modification hypothesis in the development of atherosclerosis.
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PMID:Isoprostanes and other markers of peroxidation in atherosclerosis. 1629 8

Aim of this study was to analyse the relationship between the plasma levels of polyphenols and the antioxidant activity of red and white wine. Twenty healthy subjects (HS) were randomly allocated to drink 300 ml of red (n = 10) or white n = 10 wine for 15 days. Ten HS who refrained from any alcohol beverage for 15 days were used as control. Urinary PGF-2alpha-III, a marker of oxidative stress and plasma levels of polyphenols were measured. Urinary PGF-2alpha-III significantly fell in subjects taking wine with a higher percentage decrease in subjects given red wine (-38.5 +/- 6%, p < 0.001) than in those given white wine (-23.1 +/- 6%). Subjects taking red wine had higher plasma polyphenols than those taking white wine (1.9 +/- 0.6 microM versus 1.5 +/- 0.33 microM, p < 0.001). Plasma polyphenols were inversely correlated with urinary PGF2alpha (r = 0.77, p < 0.001). No changes of urinary isoprostanes were observed in subjects who refrained from wine intake. In vitro study demonstrated that only a mixture of polyphenols, all in a range corresponding to that found in human circulation, inhibited LDL oxidation and PKC-mediated NADPH oxidase activation. Such inhibitory effects were more marked using the concentrations of polyphenols detected in human circulation after red wine intake. This study shows that red wine is more antioxidant than white wine in virtue of its higher content of polyphenols, an effect that may be dependent upon a synergism among polyphenols.
Atherosclerosis 2006 Sep
PMID:Polyphenols synergistically inhibit oxidative stress in subjects given red and white wine. 1631 Jan 97

Disodium disuccinate astaxanthin ('rac'-dAST; Cardax) is a water-dispersible C40 carotenoid derivative under development for oral and parenteral administration for cardioprotection of the at-risk ischemic cardiovascular patient. In experimental infarction models in animals (rats, rabbits, and dogs), significant myocardial salvage has been obtained, up to 100% at the appropriate dose in dogs. The documented mechanism of action in vitro includes direct scavenging of biologically produced superoxide anion; in vivo in rabbits, modulation of the complement activity of serum has also been shown. A direct correlation between administration of the test compound in animals and reductions of multiple, independent markers of oxidative stress in serum was recently obtained in a rat experimental infarction model. For the current study, it was hypothesized that oral Cardax administration would inhibit oxidative damage of multiple relevant biological targets in a representative, well-characterized murine peritoneal inflammation model. A previously developed mass spectrometry-based (LC/ESI/MS/MS) approach was used to interrogate multiple distinct pathways of oxidation in a black mouse (C57/BL6) model system. In vivo markers of oxidant stress from peritoneal lavage samples (supernatants) were evaluated in mice on day eight (8) after treatment with either Cardax or vehicle (lipophilic emulsion without drug) orally by gavage at 500 mg/kg once per day for seven (7) days at five (5) time points: (1) baseline prior to treatment (t=0); (2) 16 h following intraperitoneal (i.p.) injection with thioglycollate to elicit a neutrophilic infiltrate; (3) 4 h following i.p. injection of yeast cell wall (zymosan; t=16 h/4 h thioglycollate+zymosan); (4) 72 h following i.p. injection with thioglycollate to elicit monocyte/macrophage infiltration; and (5) 72 h/4 h thioglycollate+zymosan. A statistically significant sparing effect on the arachidonic acid (AA) and linoleic acid (LA) substrates was observed at time points two and five. When normalized to the concentration of the oxidative substrates, statistically significant reductions of 8-isoprostane-F(2alpha) (8-iso-F(2alpha)) at time point three (maximal neutrophil recruitment/activation), and 5-HETE, 5-oxo-EET, 11-HETE, 9-HODE, and PGF(2alpha) at time point five (maximal monocyte/macrophage recruitment/activation) were observed. Subsequently, the direct interaction of the optically inactive stereoisomer of Cardax (meso-dAST) with human 5-lipoxygenase (5-LOX) was evaluated in vitro with circular dichroism (CD) and electronic absorption (UV/Vis) spectroscopy, and subsequent molecular docking calculations were made using mammalian 15-LOX as a surrogate (for which XRC data has been reported). The results suggested that the meso-compound was capable of interaction with, and binding to, the solvent-exposed surface of the enzyme. These preliminary studies provide the foundation for more detailed evaluation of the therapeutic effects of this compound on the 5-LOX enzyme, important in chronic diseases such as atherosclerosis, asthma, and prostate cancer in humans.
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PMID:The effects of oral Cardax (disodium disuccinate astaxanthin) on multiple independent oxidative stress markers in a mouse peritoneal inflammation model: influence on 5-lipoxygenase in vitro and in vivo. 1646 47

In addition to a variety of lipids, 2 products of the arachidonic acid cascade, prostacyclin and thromboxane, are involved in the pathogenesis of atherosclerosis as a result of their effects on platelet function and on the vascular endothelium. The aim of the present investigation was to ascertain if a sub-maximal 8 week endurance training period followed by a 4 week detraining period would have any effects on high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), triglycerides (TG), 2,3-dinor-6-keto-prostaglandin F(1alpha) (2,3-dinor-6-keto-PGF(1alpha)), the urinary metabolite of prostacyclin, 2,3-dinor-thromboxane B2 (2,3-dinor-TXB2), the urinary metabolite of thromboxane, and the ratios of TC to HDL-C and of 2,3 dinor-6-keto-PGF(1alpha) to 2,3-dinor-TXB2. Thirty-eight boys aged 10-14 were randomly divided into exercise (n = 21) and control (n = 17) groups. The exercise group trained on a bicycle ergometer 4 times/week, 1 h/session, at 80% of their physical working capacity at a heart rate of 170 beats/min (PWC(170)), for 8 weeks. The control group did not participate in any specific physical exercise program. The results showed that relative to the control group, the exercise group had a significant increase in HDL-C and 2,3-dinor-6-keto-PGF(1alpha) concentrations at the end of the 4th (p < 0.05 and p < 0.001, respectively) and the 8th week (p < 0.01 and p < 0.001) of training, respectively; a significant increase in the 2,3 dinor-6-keto-PGF(1alpha) - 2,3-dinor-TXB2 ratio (p < 0.05 and p < 0.01 at the same intervals); a significant decrease in TG at the end of the 8th week of training (p < 0.05); and a significant decrease in the TC--HDL-C ratio at the end of the 4th (p < 0.05) and 8th weeks of training (p < 0.001).
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PMID:Effects of physical conditioning on lipids and arachidonic acid metabolites in untrained boys: a longitudinal study. 1690 Feb 33

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

Atherosclerosis is characterized by chronic inflammation and enrichment of inflammatory cells in the vessel wall. Acute inflammation can lead to damaged endothelium triggering the coagulation cascade and thrombus formation. Likewise, the clotting cascade may elicit an inflammatory response. The vascular endothelium regulates vascular tone, permeability, inflammation, thrombosis, and coagulation. Dysfunction of the vascular endothelium can promote atherosclerotic disease processes. Prostanoids (prostaglandins, thromboxane, and prostacyclin) have been established as inflammatory mediators in vascular endothelial function and there continues to be growing insights into their role in atherosclerotic disease. This review examines the role of prostanoids as paracrine inflammatory mediators of atherosclerotic vascular disease, highlighting the relevant physiology of eicosanoid production and endothelial dysfunction. We consider the role of prostanoids in systemic diseases associated with high cardiovascular morbidity and mortality, including diabetes mellitus, coronary artery disease, peripheral arterial disease, rheumatologic disorders, and dyslipidemia. We present emerging evidence that cardio-protective and lipid lowering medications, such as irbesartan and simvastatin may exert their effects via prostanoid mediated pathways. Both serum and urinary prostanoids may be utilized as diagnostic predictors of disease; for example 8-iso-PGF(2alpha) in the serum has recently been reported as an independent predictor of symptomatic peripheral arterial disease. In addition, we discuss current recommendations on established therapeutic uses of prostanoids for atherosclerotic diseases, such as the use of PGE(1) for the treatment of peripheral arterial disease. Finally, we investigate original therapeutic modalities of various prostanoids involved in the aforementioned diseases.
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PMID:Recent insights into the role of prostanoids in atherosclerotic vascular disease. 1707 4


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