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)

Recently two local hormones, thromboxane A2 (TXA2) and prostacyclin (PGI2) have been discovered. These hormones are labile metabolites of arachidonic acid. TXA2 is generated by blood platelets, while PGI2 is produced by vascular endothelium. TXA2 is a potent vasoconstrictor. It also initiates the release reaction, followed by platelet aggregation. PGI2 is a vasodilator, especially potent in coronary circulation. It also inhibits platelet aggregation by virtue of stimulation of platelet adenyl cyclase. Common precursors for both hormones are cyclic endoperoxides PGG2 and PGH2, being formed by cyclooxygenation of arachidonic acid. This last enzymic reaction is more efficient in platelets than in vascular endothelium, and therefore the generation of PGI2 by vasuclar wall is accelerated by an interaction between platelets and endothelial cells. During this interaction platelets supply the endothelial PGI2 synthetase with their cyclic endoperoxides. The newly formed PGI2 repels the platelets from the intima. When PGI2 synthetase is irreversibly inactivated by low concentration of lipid peroxides, then the platelets are not rejected but stick to the endothelium, generate TXA2 and mature thrombi are formed. A balance between formation and release of PGI2, TXA2 and/or cyclic endoperoxides in circulation is of utmost importance for the control of intra-arterial thrombi formation and possibly plays a role in the pathogenesis of atherosclerosis.
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PMID:A possible role of thromboxane A2 (TXA2) and prostacyclin (PGI2) in circulation. 36 54

Microsomal fractions from arterial walls of pigs and rabbits and fundus of rat stomach generate from prostaglandin endoperoxides (PGG2 or H2) an unstable substance, prostaglandin X (PGX) which is a potent inhibitor of platelet aggregation induced by several different substances. Other microsomal fractions including corpus of stomach, lung and ram seminal vesicles generate smaller amounts of PGX from PGG2 or PGH2. Incubation of microsomes from arterial wall or fundus of stomach with platelet-rich plasma under various conditions shows that the enzyme which generates PGX can utilize endoperoxides liberated from platelets or added to the cuvette, thereby preventing, interrupting or reversing the process of platelet aggregation. The generation of PGX is strongly inhibited (IC50 0.43 mug/ml) by 15-hydroperoxy arachidonic acid. These observations are important in the interpretation of vascular diseases such as atherosclerosis and thrombosis and provide a rational basis for the use of anti-oxidants in the prevention and treatment of these diseases.
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PMID:A lipid peroxide inhibits the enzyme in blood vessel microsomes that generates from prostaglandin endoperoxides the substance (prostaglandin X) which prevents platelet aggregation. 82 86

The effects of thromboxane A2 (TXA2) on the proliferation of vascular smooth muscles cells (VSMC) were examined using primary cultures of VSMC from rat aorta. U46619, a stable TXA2 mimetic, stimulated DNA synthesis of VSMC only in the presence of insulin. The effect was concentration-dependent with a half-maximal effect obtained at approximately 1 x 10(-8) M. The mitogenic effect of U46619 was larger than that of endothelin, another mitogen derived from endothelium. Among several TXA2/PGH2 analogs, the proliferative activity was detected only in the agonists, and not in the antagonists or in the metabolite of TXA2. A series of TXA2/PHG2 receptor antagonists completely suppressed the U46619-stimulated DNA synthesis as well as the [3H]SQ29,548 binding to the TXA2/PGH2 receptors in VSMC. The rank order of binding affinities to the receptors among the respective antagonists correlated well with the potencies for suppression of the proliferative effects of U46619. The mitogenic effects of U46619 were also attenuated by the presence of calcium antagonists. U46619 caused activation of phospholipase C with the production of inositol trisphosphate, leading to increases in the intracellular free Ca2+ concentration as measured with the fluorescent indicator fura-2. These results suggest that TXA2 induces mitogenic effects on VSMC through binding to its specific receptors. This effect of TXA2 on the proliferation of VSMC may be related to the development of atherosclerosis.
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PMID:Receptor-mediated mitogenic effect of thromboxane A2 in vascular smooth muscle cells. 214 80

Selenium is an essential component of glutathione peroxidase, an enzyme which protects cells against peroxidation and controls concentrations of intracellular peroxides. Since selenium deficiency is clinically associated with an increased degree of atherosclerosis, the effects of selenium deficiency on prostacyclin (PGI2) and platelet activating factor (PAF) production by cultured human umbilical vein endothelial cells (HUVEC) were investigated. In selenium-deficient HUVEC, histamine-induced PGI2 synthesis was significantly decreased when compared to selenium-supplemented HUVEC; in contrast, histamine-induced PAF production was increased by selenium deficiency. Histamine-induced inositol trisphosphate and [Ca2+]i responses and the conversion of PGG2 and PGH2 to PGI2 were not altered by selenium deficiency. However, selenium deficiency decreased the conversion of exogenous arachidonate to PGI2 and markedly suppressed glutathione peroxidase activity. These results suggest that selenium deficiency, by decreasing glutathione peroxidase activity, makes HUVEC susceptible to peroxide-induced inhibition of the cyclooxygenase activity of PGH2 synthase, resulting in decreased PGI2 production. These changes may alter platelet function in vivo and thus play a role in the increased incidence of atherosclerosis reported in selenium-deficient individuals.
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PMID:Selenium deficiency inhibits prostacyclin release and enhances production of platelet activating factor by human endothelial cells. 251 81

Atherosclerosis was induced in New Zealand White rabbits by feeding them a 0.5% cholesterol-enriched rabbit chow for 10-12 wk. Half of the cholesterol-fed rabbits were given BM 13505, a specific thromboxane A2/endoperoxide (TxA2/PGH2) receptor antagonist, and the other half were given its vehicle (i.e., 2% Na2CO3). At the end of 10-12 wk, the rabbits underwent experimental myocardial ischemia or an identical sham operation, except that the coronary artery was not occluded. BM 13505 was shown to protect the ischemic rabbit myocardium by three different methods: 1) maintenance of myocardial tissue creatine kinase (CK) activity in the ischemic myocardium; 2) reduced loss of free amino nitrogen-containing compounds from the myocardium; and 3) blunting the rise of plasma CK activity. Part of the mechanism for these effects may be due to inhibition of platelet aggregation and blockade of the vasoconstrictor effect of TxA2. However, these protective effects were not due to differences in myocardial oxygen demand among the groups. Finally, BM 13505 exhibited an antiatherogenic effect by reducing the deposition of cholesterol in the aortic wall and by retarding plaque formation in coronary arteries. However, it does not achieve this antiatherogenic effect by lowering plasma cholesterol concentrations or by scavenging superoxide free radicals. Thus blockade of TxA2 receptors exerts a variety of beneficial effects that reduce the severity of ischemic damage resulting from myocardial ischemia.
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PMID:Cardioprotective actions of thromboxane receptor antagonism in ischemic atherosclerotic rabbits. 297 Feb 33

A decrease in the formation of prostacyclin (PGI2), a potent vasodilating and platelet antiaggregatory substance, has been implicated in the pathogenesis of diabetic vasculopathy. This defect, as well as others, may contribute to imbalances in the thrombo-regulatory system resulting in enhanced platelet aggregability, accelerated atherosclerosis, and subsequent vessel injury. Until recently the major thrust of relevant literature has been directed toward abnormalities in PGI2 quantity or function in vascular tissue from experimentally induced diabetic animal models. For the past 2 years our laboratory has studied prostaglandin metabolism in human diabetic and nondiabetic blood vessels. We determined prostacyclin synthetase (PGI2ase) activity in saphenous veins of diabetic and nondiabetic patients (HSV-D and HSV-ND) undergoing coronary artery bypass grafts and in tibial arteries and tibial veins of diabetic patients (HTA-D and HTV-D) and nondiabetic patients (HTA-ND and HTV-ND) undergoing limb amputation for arterial disease of the lower extremity. Carbon 14-labeled prostaglandin endoperoxide (PGH2) was incubated for 2 minutes with vascular microsomal protein. The products were separated via thin-layer chromatography and quantified by radiochromatographic scan. PGI2ase activity was determined by the formation of 6-keto-PGF1 alpha, the stable breakdown product of PGI2. Results of this study indicate that the microsomal fractions of all vascular tissues studied contain an active PGI2ase capable of forming PGI2; formation is enzymatic, as the amount of product increased with increasing microsomal protein concentration; there is no significant difference in PGI2ase activity between HSV-D and HSV-ND; PGI2ase activity in HTA-D and HTV-D is less than in HSV-D and HSV-ND.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prostacyclin synthetase activity in human diabetic and nondiabetic vascular tissue. 352 43

A hypothesis of Gryglewski et al. explains the correlation between increased level of LDL and development of atherosclerosis by inhibition of PGI2 synthesis by increased peroxide content of LDL. The aim of the present paper was to examine this hypothesis. The major results are: 1) Preparation of LDL in the presence of .02% butylated hydroxytoluene did not reduce the lipid peroxide content of LDL from men and women and not change the inhibition or stimulation of the in vitro biosynthesis of PGI2 by LDL isolated from blood of men or women, respectively. 2) In the LDL and HDL, respectively, of healthy men we found nearly the same lipid peroxide levels (nmole malondialdehyde (MDA)/mg lipoprotein-cholesterol) as in the lipoproteins of male patients with hyperlipidemia type IIa or IV, but the peroxide concentration is three times higher in HDL as in LDL. 3) LDL isolated from healthy men inhibited in dose dependent fashion the generation of PGI2 from PGH2 by aortic microsomes whereas LDL from premenopausal women stimulated PGI2 formation even calculated as LDL lipid peroxides (in nM MDA/ml). The results call into question the hypothesis that diminished PGI2 formation by atherosclerotic vessels is related to inhibition of PGI2 synthetase by lipid peroxides present in LDL in the lesions. A new working hypothesis is presented that also the fatty acid pattern and the lipid class composition in the LDL are important for their influence on the PGI2 formation.
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PMID:Inhibition of prostaglandin I2 (PGI2) formation by LDL-cholesterol or LDL-peroxides? 639 33

We examined whether prostaglandin (PG) H2, as an endothelium-dependent contracting factor, or the disturbed production of endothelium-derived relaxing factor, impairs endothelium-dependent relaxation and whether long-term inhibition of nitric oxide (NO) synthesis aggravates atherosclerosis in hypercholesterolemic rabbits. Male New Zealand White rabbits were fed one of the following diets: (1) standard chow; (2) 2% cholesterol-supplemented chow; (3) standard chow with 80 micrograms/mL N omega-nitro-L-arginine methylester (L-NAME), an NO synthetase inhibitor, in their drinking water; or (4) 2% cholesterol-supplemented chow with 80 or 160 micrograms/mL L-NAME in their drinking water. The rabbits were fed these diets for 8 or 12 weeks. Then aortic rings were obtained, and changes in isometric tension were recorded. Intimal atherosclerotic areas of the thoracic aortas were subsequently measured by planimetry. The cholesterol-supplemented diet significantly impaired endothelium-dependent aortic relaxation to acetylcholine. Pretreatment with the thromboxane A2/PGH2 receptor antagonist ONO-3708 did not reverse this impaired response. Vessels from both normocholesterolemic and hypercholesterolemic rabbits given L-NAME showed more impaired endothelium-dependent relaxation than those from their dietary counterparts not given L-NAME. Morphometric analysis revealed marked enlargement of intimal atherosclerotic areas in aortas from L-NAME-treated hypercholesterolemic rabbits compared with those from untreated hypercholesterolemic rabbits. These findings suggest that PGH2 does not contribute to impaired endothelium-dependent relaxation and that long-term administration of L-NAME promotes atherosclerosis by inhibition of NO synthesis in the hypercholesterolemic rabbit thoracic aorta.
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PMID:Long-term inhibition of NO synthesis promotes atherosclerosis in the hypercholesterolemic rabbit thoracic aorta. PGH2 does not contribute to impaired endothelium-dependent relaxation. 817 41

Isoprostanes are eicosanoids that are non-enzymatic products of free radical catalyzed peroxidation of arachidonyl containing phospholipids (1). They are subsequently released from the site of generation as esters of phospholipid (bound) or through the action of phospholipase(s) A2 in free form (2). One F2-isoprostane whose formation is highly favored is 8-iso-PGF2 alpha which has been shown to be a potent pulmonary and renal vasoconstrictor (3,4). Actions of 8-iso-PGF2 alpha were demonstrated to be mediated through a receptor related to but probably distinct from the thromboxane (TXA2)/endoperoxide (PGH2) receptor (5). Although 8-epi-PGF2 alpha is a potent agonist of TXA2/PGH2 receptors in vascular smooth muscle, interestingly it acts primarily as an antagonist of TXA2/PGH2 receptors on both human and rat platelets (6). There is also evidence for the generation of D- and E-ring isoprostanes (7) and their receptor-mediated action on smooth muscle cells (8) and platelets (9). Recent reports support the hypothesis that E2-isoprostane receptors are distinct from TXA2/PGH2 receptors, suggesting at least different subtypes, one of these specifically recognizing E2-isoprostanes (9). Isoprostanes have been suggested to be useful markers for oxidant injury. For example, F2-isoprostanes were significantly elevated in plasma of rats during reperfusion after hepatic ischemia (10) and in patients with hepatorenal syndrome (11). It has been suggested that the release of F2-isoprostanes from oxidized LDL in macrophages could be a contributory factor in the development of atherosclerosis and at sites of inflammation, locally elevated levels of isoprostanes could contribute to blood cell activation. In this study we investigate possible pro- or antiaggregatory properties of various F- and E-type isoprostanes on human platelets.
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PMID:The influence of isoprostanes on ADP-induced platelet aggregation and cyclic AMP-generation in human platelets. 918 22

Atherogenesis is a multifactorial chronic inflammatory disease in which low plasma levels of HDLs are a strong predictor of the condition. Although the mechanism of protection by HDLs is not precisely known, HDLs have been shown to influence many of the events involved in the development of atherosclerosis. Previously we have shown that HDLs inhibited the cytokine-induced expression of adhesion molecules (E-selectin, VCAM-1, and ICAM-1) by endothelial cells (ECs). As the complete transcriptional regulation of all 3 genes requires the NF-kappaB family of transcription factors, we examined the effect of HDLs on activation of NF-kappaB. We also investigated the effect of HDLs on 2 other cytokine-induced genes, granulocyte-macrophage colony-stimulating factor (GM-CSF) and cyclooxygenase (Cox-2; prostaglandin H2 synthase, EC 0.1.14.99.1). E-selectin expression in response to tumor necrosis factor-alpha (TNFalpha) was, as expected, inhibited in ECs that had been preincubated with HDLs. However, the level of secretion of GM-CSF in the same cultures was no different from control. In a similar manner, although HDLs had no effect on steady-state mRNA levels of GM-CSF, the levels of E-selectin were significantly inhibited by HDLs. In transient cotransfection experiments we found that HDLs inhibited the cytokine-induced expression of a reporter gene driven by the E-selectin proximal promoter (-383 to 80) but had no effect on the expression of a reporter gene driven under the control of the proximal promoter of GM-CSF (-627 to 28). As would be predicted from this differential response, HDLs did not influence the nuclear translocation or DNA binding of NF-kappaB, or alter the kinetics of degradation and resynthesis of the inhibitory protein IkappaBalpha. We found that HDLs synergized with cytokine to enhance the expression of Cox-2 and induce the synthesis of its main EC product, prostacyclin (PGI2), a potent inhibitor of platelet and leukocyte functions. In conclusion, HDL induces an antiinflammatory phenotype in cytokine-induced ECs, synergizing with cytokine to induce elevation of Cox-2 in addition to inhibiting adhesion molecule expression. Our studies show that these differential effects are mediated in a manner that is likely to be independent of NF-kappaB per se.
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PMID:High-density lipoproteins differentially modulate cytokine-induced expression of E-selectin and cyclooxygenase-2. 1019 17


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