Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Nitrate-based vasodilators (NBVs) are commonly used to treat multiple sequelae of atherosclerosis. A commonly used NBV, glyceryl trinitrate (GTN) is bioactivated by mitochondrial, class 2 aldehyde dehydrogenase (ALDH2). ALDH2 and other ALDHs are NAD(P)+-dependent enzymes critical to the detoxification of cytotoxic lipid-aldehydes elevated in atherosclerotic lesions, such as trans-4-hydroxy-2-nonenal (HNE). The GTN bioactivation step, however, inac-tivates ALDH2 and may alter the metabolism of these aldehydes. In this study, we tested the hypothesis that multiple ALDH enzymes are inhibited by different NBVs. ALDH2, ALDH3A, and ALDH5A were present in aorta with ALDH2 and ALDH3A localized to the smooth muscle layers. GTN (1 microM) inhibited ALDH2 activity (55 +/- 6% of control) and ablated ALDH3 activity. In contrast, isosorbide-2,5-dinitrate (ISDN, 1 microM) inhibited ALDH3 activity (1.1 +/- 0.4% of control) but did not inhibit ALDH2 activity even up to 50 microM ISDN. In homogenates of rat aorta, GTN (1 microM) inhibited the NAD+-dependent (41 +/- 5% of control) and NADP+-dependent (25 +/- 6% of control) detoxification of HNE. The inhibition of ALDH3A, but not ALDH2, could be prevented by the addition of dithiothreitol. These studies demonstrate that GTN and ISDN possess selectivity for ALDH inactivation with different mechanisms of inactivation.
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PMID:Nitrate-based vasodilators inhibit multiple vascular aldehyde dehydrogenases. 1624 77

Triflusal is an antiplatelet drug related to aspirin, with different pharmacological properties and a lower haemorrhagic risk. We aimed at comparing their effects on platelet and endothelial activation in type 2 diabetes mellitus (T2DM). In a randomized, double-blind, parallel group study, we compared the effects of three daily regimens (300, 600, and 900 mg) of triflusal, and aspirin (100mg/day) on urinary 11-dehydro-thromboxane (TX)B(2), index of in vivo platelet activation, ex vivo platelet function using the analyzer PFA-100, plasma von Willebrand factor (vWF), P-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and serum nitrite and nitrate (NO(2)(-)+NO(3)(-)) in 60 T2DM patients. Triflusal induced a dose-dependent reduction in 11-dehydro-TXB(2) and a prolongation of closure time in the presence of collagen plus epinephrine (Coll/Epi-CT). The effects of the highest triflusal dose were not different from those of aspirin. The closure time in the presence of collagen plus ADP (Coll/ADP-CT), ICAM-1, VCAM-1, and NO(2)(-)+NO(3)(-) were not modified either by triflusal or aspirin. Plasma P-selectin and vWF were reduced by triflusal but not by aspirin. In T2DM triflusal causes a profound inhibition of platelet TXA(2) biosynthesis in vivo, acting on different targets involved in the platelet-endothelial cell interactions.
Atherosclerosis 2005 Dec
PMID:Inhibition of thromboxane biosynthesis by triflusal in type 2 diabetes mellitus. 1628 96

cGMP-dependent protein kinase (PKG) is the major intracellular receptor for cyclic guanosine monophosphate (cGMP). Two forms of PKG, PKG-I and PKG-II, occur in mammalian tissues. PKG may mediate nitric oxide-cGMP-induced vasodilation through decreasing intracellular calcium concentration by the activation of calcium-activated potassium channel on the cell membrane and phosphorylation of phospholamban (PLB) and IP3 receptor-associated PKG-I substrate (IRAG) on the sarcoplasmic reticulum. PKG may also decrease the sensitivity of myosin to calcium by stimulating the activity of myosin light chain phosphatase and by inhibiting Rho kinase activity. PKG plays an important role in regulating the gene expression, phenotype, and proliferation of vascular smooth muscle cells. PKG activation inhibits platelet aggregation and myocardial hypertrophy. Recent studies indicate that the alternations of PKG expression and activity are closely related with the pathogenesis of atherosclerosis, restenosis, hypertension, hyperlipemia as well as nitrate tolerance.
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PMID:[Role of cGMP-dependent protein kinase in the cardiovascular system]. 1640 66

Fasting hypertriglyceridemia relates with high-density lipoprotein (HDL) cholesterol, but it is not known whether low HDL cholesterol is associated with disturbances of chylomicron metabolism. To clarify this issue this metabolism was studied in subjects with low HDL cholesterol together with vascular reactivity and evaluation of no-flush niacin treatment. Thirty men with HDL < 1.04 mmol/L and no other risk factors for coronary artery disease (CAD) and 11 normal controls with HDL > 1.04 mmol/L were studied. The plasma kinetics of a chylomicron-like emulsion labeled with 14C-cholesterol oleate (CO) and 3H-triolein (TG) was determined and the fractional clearance rate (FCR, min(-1)) was calculated. Vascular reactivity was evaluated using high-resolution ultrasonography. CO FCR was markedly reduced in the low HDL group compared to controls (3.6 x 10(-3) +/- 5.1 x 10(-3) min(-1) versus 12.2 x 10(-3) +/- 8.4 x 10(-3) min(-1), p < 0.001) but TG FCR was similar. Flow-mediated dilation (FMD) was diminished in low HDL (7.4 +/- 4.1 versus 12.8 +/- 4.6%, p < 0.001), whereas nitrate-mediated dilation was similar. Twenty-two low HDL subjects with reduced FMD were randomized into two groups, one given 1.5 g/day niacin and a placebo group. After 3-month treatment, plasma lipids and chylomicron kinetics were not changed by niacin treatment but FMD improved to normal values (5.44 +/- 1.89 to 11.13 +/- 3.4%, p < 0.01). In conclusion, isolated low HDL cholesterol subjects may also bear chylomicron remnant accumulation and endothelial dysfunction, which highlight the importance of their preventive treatment.
Atherosclerosis 2006 Jul
PMID:Accumulation of chylomicron remnants and impaired vascular reactivity occur in subjects with isolated low HDL cholesterol: effects of niacin treatment. 1645 16

We evaluated the plasma homocysteine (tHcy) and nitric oxide metabolites (nitrite plus nitrate; NOx) data of consecutive patients undergoing diagnostic coronary angiography (n=79) with respect to the presence and severity of coronary artery disease (CAD), the presence of acute coronary syndromes (ACS), and the risk status of patients. Hyperhomocysteinemia (>15 micromol/L) was detected in 11% of the controls (n=19) and 37% of CAD patients (n=60) (p=0.03). Plasma tHcy in CAD patients was not significantly different from controls, but those with 3-vessel disease had a significantly higher tHcy concentrations than did controls (p=0.049). The patients with 3-vessel disease and ACS had the highest concentrations of tHcy (16.9 +- 4.4 micromol/L), and the difference from the ACS patients with 1- and 2-vessel involvement was significant (p=0.03). In patients with 1-vessel involvement, tHcy was correlated with NOx (r=0.62, p=0.005); in patients with 2- and 3-vessel disease this correlation could not be observed. The high-risk patients (n=51) had a higher mean number of vessel involvement and tHcy (p<0.001, p<0.05, respectively) but lower NOx (p<0.05) when compared to the low-risk patients (n=28). It appears that in the early stages of atherosclerosis hyperhomocysteinemia causes an increase in NOx production, but with progression of the disease this compensatory increase disappears.
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PMID:Homocysteine and nitric oxide in patients undergoing diagnostic coronary angiography. 1650 87

Obesity is associated with vascular endothelial cell dysfunction (ECD). Studies on nitric oxide (NO) production of vascular system in these subjects may help delineate the pathogenesis of obesity-associated ECD. In this study, we recruited 69 severely obese patients who were treated with gastric partition surgery for weight reduction and 69 matched healthy controls for comparison. The following parameters were obtained in the healthy control subjects and in the obese subjects both before and after gastric partition surgery: body mass index, blood pressure, serum lipids, high sensitivity C-reactive protein (hs-CRP), adiponectin, total nitrite and nitrate (NO(x)), and 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), and insulin resistance index (as measured by homeostasis model assessment (HOMA-IR). At baseline, serum lipids, glucose, insulin, hs-CRP and 8-iso-PGF2alpha and HOMA-IR were all higher while adiponectin lower in the obese group than in the control group. The serum NO(x) levels were not different between the two groups. In the obese subjects, the adiponectin levels were significantly elevated but NO(x) markedly decreased after surgery. All other measurements, except for systolic blood pressure, were decreased after surgery. For healthy controls, the serum NO(x) levels were negatively associated with HOMA-IR and positively associated with serum adiponectin levels as analyzed by multiple linear regression analysis. In obese patients, the baseline serum NO(x) was positively associated with the serum TG levels. The changes of serum NO(x) levels after weight reduction surgery were positively associated with the changes of body mass index and serum TG levels. These observations suggested that, in the extremely obese patients, there might be excessive production and/or inactivation of NO and, after weight reduction surgery, the NO production was down-regulated. In conclusion, in the severely obese patients, the apparently normal NO production might be due to over-expression of iNOS. After gastric partition surgery, the NO production was significantly decreased which might be reflecting the usual status of NO production in obese subjects. The positive correlation between NO(x) and serum TG level might suggest that the metabolism of TG plays a role in the regulation of NO production.
Atherosclerosis 2007 Feb
PMID:Nitric oxide production is paradoxically decreased after weight reduction surgery in morbid obesity patients. 1654 95

Endothelial dysfunction characterizes many disease states including subclinical atherosclerosis. The consumption of flavanol-rich cocoa and cocoa-based products has been shown to improve endothelial function in both compromised and otherwise normal, healthy individuals when administered either acutely or over a period of several days, or weeks. Women experience increased risk for cardiovascular disease after menopause, which can be associated with endothelial dysfunction. Whether a flavanol-rich cocoa-based product can improve endothelial function in hypercholesterolemic postmenopausal women is not known. The purpose of the present study was to determine whether chronic dietary administration of flavanol-rich cocoa improves endothelial function and markers of cardiovascular health in hypercholesterolemic postmenopausal women. Thirty-two postmenopausal hypercholesterolemic women were randomly assigned to consume a high-flavanol cocoa beverage (high cocoa flavanols (CF)--446 mg of total flavanols), or a low-flavanol cocoa beverage (low CF--43 mg of total flavanols) for 6 weeks in a double-blind study (n=16 per group). Endothelial function was determined by brachial artery-reactive hyperemia. Plasma was analyzed for lipids (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol), hormones (follicle-stimulating hormone), total nitrate/nitrite, activation of cellular adhesion markers (vascular cell adhesion molecule 1, intercellular adhesion molecule 1, E-Selectin, P-Selectin), and platelet function and reactivity. Changes in these plasma markers were then correlated to brachial reactivity. Brachial artery hyperemic blood flow increased significantly by 76% (P<0.05 vs. baseline) after the 6-week cocoa intervention in the high CF group, compared with 32% in the low CF cocoa group (P=ns vs. baseline). The 2.4-fold increase in hyperemic blood flow with high CF cocoa closely correlated (r2=0.8) with a significant decrease (11%) in plasma levels of soluble vascular cell adhesion molecule-1. Similar responses were not observed after chronic use of low CF. There were no significant differences between high and low CF in other biochemical markers and parameters measured. This study is the first to identify beneficial vascular effects of flavanol-rich cocoa consumption in hypercholesterolemic postmenopausal women. In addition, our results suggest that reductions in plasma soluble vascular cell adhesion molecule-1 after chronic consumption of a flavanol-rich cocoa may be mechanistically linked to improved vascular reactivity.
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PMID:Chronic consumption of flavanol-rich cocoa improves endothelial function and decreases vascular cell adhesion molecule in hypercholesterolemic postmenopausal women. 1679 56

Diet patterns are widely recognized as contributors to hypertension. Widely studied potential contributors include intake of sodium, potassium, magnesium, calcium, soluble fiber, omega-3 fatty acids, alcohol, protein, and calories. We add to that list the effect of dietary flavanols present in certain cocoas, which have sufficient activity on vascular nitric oxide to influence blood pressure control. Kuna Indians who live on islands near Panama have little age-related rise in blood pressure or hypertension. On migration to Panama City, blood pressure rises with age, and the frequency of essential hypertension matches urban levels elsewhere. We have identified a specific food that probably makes an important contribution to cardiovascular status. Island-dwelling Kuna drink more than 5 cups of flavanol-rich cocoa per day and incorporate that cocoa into many recipes. Mainland Kuna ingest little cocoa, and what they take is commercially available and flavanol-poor. The flavanol-rich cocoa activates nitric oxide synthase in vitro and in intact humans in the doses that the Kuna employ. Vasodilator responses to flavonoid-rich cocoa are prevented or reversed by the arginine analog, N-nitro-L-arginine methyl ester. Island-dwelling Kuna have a 3-fold larger urinary nitrate:nitrite than do Mainland dwellers. As endothelial dysfunction is central to current thinking on cardiovascular pathophysiology, a food that enhances endothelial function could have broad implications. The list of candidate conditions that might be influenced is impressive, ranging from atherosclerosis and diabetes mellitus to hypertension and preeclampsia, to vascular dementias and end-stage renal disease. The next decade will be interesting.
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PMID:Vascular action of cocoa flavanols in humans: the roots of the story. 1679 63

Oxidized low-density lipoprotein (OxLDL) impairs NO signaling and endothelial function, and contributes to the pathogenesis of atherosclerosis. Arginase reciprocally regulates NO levels in endothelial cells by competing with NO synthase for the substrate l-arginine. In human aortic endothelial cells, OxLDL stimulation increased arginase enzyme activity in a time- and dose-dependent manner. Arginase activity reached its maximum as early as 5 minutes, was maintained for a period of more than 48 hours, and was associated with a reciprocal decrease in NO metabolite (NOx [nitrite and nitrate]) production. Furthermore, OxLDL induced arginase II mRNA expression after 4 hours. Small interfering RNA targeted to arginase II decreased both the quantity and the activity of arginase from baseline, prevented OxLDL-dependent increases in arginase activity, and induced an increase in NOx production. Immunofluorescence analysis revealed an association of arginase II with the microtubule cytoskeleton. Microtubule disruption with nocodazole caused a dramatic redistribution of arginase II to a diffuse cytosolic pattern, increased arginase activity, and decreased NOx production, which was restored in the presence of the specific arginase inhibitor (S)-(2-boronoethyl)-l-cysteine (BEC). On the other hand, epothilone B prevented microtubule disruption and inhibited OxLDL-dependent increases in arginase activity and attenuated OxLDL-dependent decreases in NOx. Preincubation of rat aortic rings with OxLDL resulted in an increase in arginase activity and a decrease in NOx production. This was reversed by arginase inhibition with the BEC. Thus, OxLDLs increase arginase activity by a sequence of regulatory events that involve early activation through decreased association with microtubules and a later increase in transcription. Furthermore, increased arginase activity contributes to OxLDL-dependent impairment of NOx production. Arginase, therefore, represents a novel target for therapy in atherosclerosis.
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PMID:Oxidized low-density lipoprotein-dependent endothelial arginase II activation contributes to impaired nitric oxide signaling. 1706 98

Schimke-immuno-osseous dysplasia (SIOD) is an autosomal recessive disorder with the main clinical findings of spondyloepiphyseal dysplasia, nephrotic syndrome, and defective cellular immunity. Vaso-occlusive processes, especially generalized atherosclerosis, are a life-limiting complication in patients with severe SIOD. The nitric oxide synthase (NOS) oxidizes L-arginine to nitric oxide (NO). NO is a potent vasodilator with inhibitory effects on platelet aggregation and the development of atherosclerosis. We hypothesized that reduced NO production due to antagonism of NOS by asymmetric dimethylarginine (ADMA) would be a possible pathophysiological mechanism for vaso-occlusion in SIOD. We tested this hypothesis in 10 patients with SIOD and 10 age-matched healthy controls. Plasma and urine levels of nitrite and nitrate, the indicators of NO synthesis, and of ADMA, an endogenous NOS inhibitor, in children suffering from SIOD were not significantly different from those in the age-matched healthy controls. Our results suggest that the L-arginine/NO pathway is not altered in SIOD. Antagonism of NOS by ADMA does not seem to be the cause of premature general atherosclerosis in SIOD. The underlying pathology of vaso-occlusion in SIOD still remains unclear.
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PMID:Vaso-occlusion in Schimke-immuno-osseous dysplasia: is the NO pathway involved? 1707 78


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