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)

Strain C57BL/6J and A/J differ at two genes determining atherosclerosis susceptibility. The first gene, Ath-1, was described earlier and this report characterizes Ath-2. The alleles at Ath-2 are r for resistance and s for susceptibility to atherosclerosis. The resistant phenotype in female mice is characterized by high plasma high density lipoprotein-cholesterol levels (74 mg/dl +/- SEM 2) and very few lesions/mouse after 14 weeks of consumption of an atherogenic diet (0.1 +/- SEM 0.1 in a predetermined region of the aorta). The susceptible phenotype in female mice is characterized by low levels of high density lipoprotein-cholesterol (35 mg/dl +/- SEM 1) and 1.2 lesions/mouse +/- SEM 0.2 in the same region of the aorta. In Ath-2 heterozygotes, resistance is dominant to susceptibility. Recombinant inbred strains derived from C57BL/6 and A were characterized for Apoa 1, Apoa 2 and susceptibility to atherosclerosis. Ath-1 and Ath-2 interact with each other so that resistant alleles at either locus confer a resistant phenotype to the animal. The map position of Ath-2 is not known, but Ath-2 does not map near genes determining the apolipoproteins for A-I, A-II, or E.
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PMID:Ath-2, a second gene determining atherosclerosis susceptibility and high density lipoprotein levels in mice. 249 15

Some endothelial-injury syndromes, including atherosclerosis, may involve herpes simplex virus (HSV) infection. Examining the mechanism of injury, we found adherence of unstimulated granulocytes to HSV infected endothelium to be twice that to uninfected endothelium (34.8 +/- 1.1 versus 18.8 +/- 0.5%; mean +/- SEM; p less than 0.001) which further increased in the presence of anti-HSV antibodies. Enhanced adhesion was accompanied by excessive granulocyte-mediated lysis of 51Cr-labeled, HSV-infected endothelium (16.4 +/- 0.9%, HSV-infected versus 0.9 +/- 4.5% for uninfected endothelium; p less than 0.01). HSV infection also increased granulocyte-mediated endothelial cell detachment from its substratum (14.7 +/- 1.7% versus 3.3 +/- 0.3% for uninfected endothelium; p less than 0.001), which further increased (p less than 0.01) in the presence of immune complexes (IgG-sensitized erythrocytes). This suggests that neo-Fc receptors of infected endothelium bind IgG-coated particles, which, in turn, attract and stimulate granulocytes. In support, granulocyte-mediated detachment was not enhanced by immune complexes if endothelium was infected with a mutant HSV strain (E3/3) that does not produce glycoprotein E, the viral glycoprotein having Fc-receptor activity. Exaggerated endothelial detachment correlated with poor binding of infected endothelial cells to the substratum matrix protein, fibronectin. Resuspended, virus-infected endothelial cells bound significantly less well to tissue-culture wells coated with both low (p less than 0.001) and high (p less than 0.05) concentrations of fibronectin as compared with uninfected endothelial cells, a dichotomy further worsened in the presence of granulocyte-released elastase. We conclude that HSV-infected human endothelium is vulnerable to granulocyte-mediated injury by opposing alterations in its adhesive properties: its increased binding of granulocytes and its weakened tethering to matrix fibronectin, particularly when exposed to secreted granulocyte proteases, such as elastase.
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PMID:Granulocyte-mediated injury to herpes simplex virus-infected human endothelium. 253 63

Two groups of African green monkeys were fed diets containing 40% of calories as fat with half of the fat calories as either fish oil or lard. The fish oil-fed animals had lower cholesterol concentrations in blood plasma (33%) and low density lipoproteins (LDL) (34%) than did animals fed lard. Size and cholesteryl ester (CE) content of LDL, strong predictors of coronary artery atherosclerosis in monkeys, were significantly less for the fish oil-fed animals although the apoB and LDL particle concentrations in plasma were similar for both diet groups. We hypothesized that decreased hepatic CE secretion led to the smaller size and reduced CE content of LDL in the fish oil-fed animals. Hepatic CE secretion was studied using recirculating perfusion of monkey livers that were infused during perfusion with fatty acids (85% 18:1 and 15% n-3) at a rate of 0.1 mumol/min per g liver. The rate of cholesterol secretion was less (P = 0.055) for the livers of fish oil versus lard-fed animals (3.3 +/- 0.5 vs. 6.0 +/- 1.2 mg/h per 100 g, mean +/- SEM) but the rate of apoB secretion was similar for both groups (0.92 +/- 0.15 vs. 1.01 +/- 0.13 mg/h per 100 g, respectively). The hepatic triglyceride secretion rate was also less (P less than 0.05) for the fish oil-fed animals (8.3 +/- 2.5 vs. 18.3 +/- 4.4 mg/h per 100 g). Liver CE content was lower (P less than 0.006) in fish oil-fed animals (4.1 +/- 0.8 vs. 7.4 +/- 0.7 mg/g) and this was reflected in a lower (P less than 0.04) esterified to total cholesterol ratio of perfusate VLDL (0.21 +/- 0.045 vs. 0.41 +/- 0.06). The hepatic VLDL of animals fed fish oil had 40-50% lower ratios of triglyceride to protein and total cholesterol to protein. From these data we conclude that livers from monkeys fed fish oil secreted similar numbers of VLDL particles as those of lard-fed animals although the hepatic VLDL of fish oil-fed animals were smaller in size and relatively enriched in surface material and depleted of core constituents. Positive correlations between plasma LDL size and both hepatic CE content (r = 0.87) and hepatic VLDL cholesterol secretion rate (r = 0.84) were also found.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Fish oil decreases hepatic cholesteryl ester secretion but not apoB secretion in African green monkeys. 261 56

We have recently shown that red blood cells can induce spontaneous platelet aggregation (SPA) in whole blood ex vivo, which could be inhibited by dipyridamole. Since this drug, at therapeutic doses is not an effective inhibitor of platelet aggregation in platelet rich plasma, the inhibition of platelet interaction with the red cell was thought to be the mechanism of its action. Values for the percentage fall in the single platelet count due to SPA in whole blood after 3 and 6 min rollermixing were: control 15 +/- 2.2 and 42 +/- 2.9; 6 microM dipyridamole 6 +/- 1.1 (P less than 0.001) and 31 +/- 2.6 (P less than 0.01); 12 microM dipyridamole 2 +/- 0.9 (P less than 0.0005) and 22 +/- 2.3 (P less than 0.0005) (mean +/- SEM, n = 10). Electron microscopic observation revealed that the aggregation involves an initial platelet adhesion to the red blood cell; the adherent platelets then become activated and serve as foci for the growing aggregates. Dipyridamole appeared to inhibit the initial platelet adhesion to the red cell (the principal trigger mechanism for SPA) which may mimic the initiation of thrombosis in some situations in vivo. The inhibitory effect of dipyridamole on the platelet-red cell interaction suggests that this drug has antithrombotic potential in situations where red blood cells have a trigger role in platelet activation and may explain why the drug has been more effective in some situations than in others.
Atherosclerosis 1989 Apr
PMID:Dipyridamole inhibits red cell-induced platelet activation. 273 Jul 12

Dietary marine oil supplements may protect against atherosclerosis, although their influence on plasma lipids, in vivo cholesterol metabolism, and aortic cholesterol accumulation remains uncertain. The effects of daily administration of marine oil--delivering 100 mg of eicosapentaenoic acid, 59 mg of docosahexaenoic acid, and 221 mg of omega-3 fatty acids per kilogram--were assessed in 33 New Zealand white rabbits. Six animals (group I) were immediately killed. In the remaining animals stable hypercholesterolemia was induced with a 0.25% cholesterol-enriched diet. After 7 weeks on this diet, six animals were killed (group II). Total plasma cholesterol had increased significantly (982 +/- 119 mg/dl vs. 55.6 +/- 7.1 mg/dl, mean +/- SEM, p less than 0.001). The remaining animals randomly received a tap-water placebo (group III, n = 12) or marine oil (group IV, n = 9) daily. After 3 months, total plasma cholesterol was similar (p = NS) among group II (982 +/- 119 mg/dl), group III (965 +/- 54 mg/dl), and group IV (913 +/- 46 mg/dl). No significant differences in HDL cholesterol, LDL cholesterol, VLDL cholesterol, or triglyceride levels developed between the placebo and marine oil groups. Two-hour, hepatic total lipid, neutral steroid, fatty acid, bile acid, and cholesterol synthesis rates were not significantly affected by marine oil treatment. Thoracic aortic cholesterol content increased during cholesterol feeding (5.7 +/- 0.9 mg/gm vs. 1.1 +/- 0.05 mg/gm, group II vs. group I, p less than 0.05). Marine oil supplementation had no effect on the progressive accumulation of cholesterol in the thoracic aorta (28.8 +/- 2.5 mg/gm vs. 29.4 +/- 1.8 mg/gm, group IV vs. group III, p = 0.84). The abdominal aortic cholesterol contents were also similar. These results do not support the use of dietary marine oil supplements for the amelioration of lipid metabolism or the prevention of atherosclerosis.
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PMID:Dietary marine oil supplements fail to affect cholesterol metabolism or inhibit atherosclerosis in rabbits with diet-induced hypercholesterolemia. 276 25

Favorable changes in lipoproteins, inhibition of platelet aggregation, reduction of serum thromboxane (TX), altered plasma-membrane fluidity, and reduced production of growth factors (mitogens) have all been implicated as possibly being involved in the inhibition of arteriosclerosis by fish oil (FO), which is rich in omega 3 fatty acids; however, causal relations are mostly lacking. Several putative mechanisms responsible for the salutary effects of FO were investigated in a canine model of accelerated vein-graft arteriosclerosis. Venoarterial autografts (N = 192) were implanted in 48 hypercholesterolemic dogs divided into six groups: group A, control; B, FO (as MaxEPA, 200 mg/kg/day eicosapentaenoic acid); C, aspirin (ASA, 50 mg/kg/day); D, TX synthetase inhibitor (TXSI [CGS-12970], 10 mg/kg/day); E, FO + ASA; and F, FO + TXSI. At sacrifice 3 months later, there was no significant difference in plasma lipoproteins, hepatic low density lipoprotein-receptor concentration, red blood cell fragility, bleeding time, or platelet count compared with controls; the decrease in platelet aggregation (30 +/- 5% [mean +/- SEM]) was similar in all treatment groups. Arterialized vein-graft intimal thickening was significantly inhibited by FO (with or without ASA), while ASA alone was ineffective. Conversely, serum TX was significantly lower only in the ASA and FO + ASA groups. Serum mitogenic activity was higher at 3 months in the control group versus all treatment groups. Compared with baseline values, serum mitogenic activity rose significantly over time in the control and the TXSI groups, and an increase or rising trend was present in all other treatment groups except for the FO-treated animals. Thus, the salutary biologic effect of FO in this hypercholesterolemic model of arterialized vein grafts may have been more related to in vivo inhibition of platelet-mitogen growth factor release than to changes in lipoproteins, low density lipoprotein receptors, platelet function, or eicosanoid metabolism. These observations underscore the need for further studies to clarify the interactions between FO (omega 3 fatty acids) and paracrine cellular mitogenic factors in the context of atherosclerosis prevention.
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PMID:Mechanisms responsible for inhibition of vein-graft arteriosclerosis by fish oil. 276 20

The long term efficacy of granulated guar gum, 15-30 g per day, was studied in 23 patients with severe hypercholesterolaemia (serum cholesterol concentration between 8.0 and 14.3 mmol/l). Originally, 29 patients participated in the study. Two patients dropped out because of gastrointestinal side effects, two others were not willing to complete the study without any given reason, and two discontinued the study because of hospitalization. A 1-month placebo period preceded the guar gum treatment, and another 1-month placebo period followed after 50 weeks of active treatment. The serum total cholesterol concentration (mean +/- SEM) was reduced from 10.0 +/- 0.4 mmol/l to 8.2 +/- 0.3 mmol/l (P less than 0.001) after 8 weeks and to 9.0 +/- 0.4 mmol/l (P less than 0.001) after 50 weeks on guar gum. During the second placebo period serum cholesterol returned to the pretreatment level. After 34 weeks of active treatment the serum LDL-cholesterol concentration had fallen by 15% and that of apoprotein B by 14% from the baseline. The changes in lipid and lipoprotein levels were independent of the initial values and the type of hypercholesterolaemia. Serum triglycerides, HDL-cholesterol, body weight and blood pressure showed no significant changes during the trial. Of the study subjects, 20 reached the maximum intended dose of 30 g per day guar gum between 8 and 14 weeks and thereafter 11 subjects continued the dose of 30 g/day while 12 subjects reduced the dose to 15-25 g/day.(ABSTRACT TRUNCATED AT 250 WORDS)
Atherosclerosis 1988 Aug
PMID:Long term treatment of severe hypercholesterolaemia with guar gum. 285 Aug 7

25 of a group of 87 White men had Msp 1 restriction site polymorphism within an Alu sequence 3' to the human apo AII gene. Homozygosity for the polymorphism in 8 men was associated with a significant increase in serum apo AII levels (35.4 +/- 1.70 mg/dl, mean +/- SEM) and altered HDL composition, compared with heterozygotes (31.7 +/- 1.29; n = 17) and normal subjects (29.4 +/- 0.64; n = 62). This is the first account of a common variant of an HDL apoprotein gene that affects HDL composition. In view of its association with a high apo AII concentration homozygosity may protect against atherosclerosis.
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PMID:High-density lipoprotein composition is altered by a common DNA polymorphism adjacent to apoprotein AII gene in man. 285 63

In monkeys with early and advanced atherosclerosis, we examined responses to the three major vasoactive agonists that are released when platelets aggregate. Measurements were obtained in normal cynomolgus monkeys and in monkeys fed an atherogenic diet for 4 +/- 1, 9 +/- 1, and 19 +/- 1 months (mean +/- SEM). Morphometry of femoral and iliac arteries indicated that 4 months of atherogenic diet produced only slight intimal thickening, 9 months produced early lesions, and 19 months produced approximately 5-10 fold greater intimal proliferation than did 9 months of atherogenic diet. Serotonin and adenosine 5'-diphosphate (ADP), which are endothelium-dependent agonists, and adenosine and phenylephrine, which are endothelium-independent agonists, were injected intra-arterially into the perfused hind limb. Thromboxane A2 analogue U46619 also was studied. Vasoconstrictor responses to serotonin were potentiated, and vasodilator responses to ADP were impaired by early and advanced atherosclerosis. In contrast, vasoconstrictor responses to phenylephrine and vasodilator responses to adenosine were similar in all groups. Vasoconstrictor responses to U46619 were potentiated by advanced atherosclerosis. Thus, vascular responses to serotonin, ADP, and thromboxane A2 are altered by atherosclerosis in a direction that would favor vasoconstriction when platelets aggregate. Furthermore, because responses to endothelium-dependent agonists are altered, these data suggest that endothelium is dysfunctional in early atherosclerosis. These findings may explain, in part, the propensity for exaggerated vasoconstriction even in arteries with minimal atherosclerotic lesions.
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PMID:Effect of early and advanced atherosclerosis on vascular responses to serotonin, thromboxane A2, and ADP. 291 93

The goal of our study was to examine the effects of infusion of serotonin and the thromboxane A2 analogue U46619 into one carotid artery to stimulate their release from platelets during aggregation. We measured blood flow to the brain and eye using microspheres and cerebral microvascular pressure in the pial arteries of normal and atherosclerotic cynomolgus monkeys. Unilateral intracarotid infusion of 10-30 micrograms/min serotonin did not affect cerebral blood flow in normal or atherosclerotic monkeys; serotonin did not alter blood flow to the eye in normal monkeys but decreased flow to the retina and choroid in atherosclerotic monkeys by 39 +/- 11% and 44 +/- 10% (mean +/- SEM), respectively. Infusion of 30 ng/min U46619 did not alter cerebral blood flow but increased the pressure gradient from the aorta to the pial artery, which is an index of large-artery resistance, in atherosclerotic monkeys. U46619 had no effect on blood flow to the eye in normal monkeys but decreased blood flow to the retina and choroid by 71 +/- 14% and 53 +/- 13%, respectively, in atherosclerotic monkeys. Thus, atherosclerosis potentiates the constrictor responses of large cerebral arteries to thromboxane and the responses of blood vessels of the eye to thromboxane and serotonin.
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PMID:Atherosclerosis potentiates constrictor responses of cerebral and ocular blood vessels to thromboxane in monkeys. 291 13


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