Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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.
 ...
PMID:A possible role of thromboxane A2 (TXA2) and prostacyclin (PGI2) in circulation. 36 54

There is a great resemblance in the sequence of events that take place in the pathological development of intimal thickening, so called arteriosclerosis and the formation of intimal cushions in both the normal ductus arteriosus (DA) and the persistent ductus arteriosus (PDA). The human DA was used as a model to study the changes in the extracellular matrix during this process with immunohistochemistry. The formation of intimal cushions was studied in 4 normal fetal DA, 4 normal mature DA and 3 persistent DA. The process of intimal thickening in the fetus starts in the second trimester of pregnancy with an accumulation of glycosaminoglycans in the subendothelial region (SER), accompanied by separation of endothelial cells from the internal elastic lamina and followed by migration of smooth muscle cells into the subendothelial region. This phenomenon was also observed in the mature DA in the neonate, indicating that cushion formation is a continuous process. Intimal cushions had also developed in the persistent DA, although they were morphologically different from the cushions found in the normal mature DA. It was remarkable that two elastic lamellae could be distinguished: one at the original site on the borderline of intimal cushion and media and the other in a subendothelial position. The endothelial cells were firmly attached to this subendothelial lamina, which was wrapped in the basal lamina components laminin and type IV collagen. The main morphological difference between the normal mature DA and the persistent DA is the close relation between endothelial cells and the subendothelial elastic lamina, suggesting an altered elastin metabolism in the PDA. PGI2 synthase was increased in the wall of both the normal and persistent DA as compared with the aorta. It may be related to a role of PGI2 in the formation of intimal cushions.
Atherosclerosis 1992 Mar
PMID:Formation of intimal cushions in the ductus arteriosus as a model for vascular intimal thickening. An immunohistochemical study of changes in extracellular matrix components. 159 2

Oxidative damage to the vascular endothelium may play an important role in the pathogenesis of atherosclerosis and aging, and may account in part for reduced vascular prostacyclin (PGI2) synthesis associated with both conditions. Using H2O2 to induce injury, we investigated the effects of oxidative damage on PGI2 synthesis in cultured endothelial cells (EC). Preincubation of EC with H2O2 produced a dose-dependent inhibition (inhibitory concentration [IC50] = 35 microM) of PGI2 formation from arachidonate. The maximum dose-related effect occurred within 1 min after exposure although appreciable H2O2 remained after 30 min (30% of original). In addition, H2O2 produced both a time- and dose-dependent injury leading to cell disruption, lactate dehydrogenase release, and 51Cr release from prelabeled cells. However, in dramatic contrast to H2O2 effects on PGI2 synthesis, loss of cellular integrity required doses in excess of 0.5 mM and incubation times in excess of 1 h. The superoxide-generating system, xanthine plus xanthine oxidase, produced a similar inhibition of PGI2 formation. Such inhibition was dependent on the generation of H2O2 but not superoxide in that catalase was completely protective whereas superoxide dismutase was not. H2O2 (50 microM) also effectively inhibited basal and ionophore A23187 (0.5 microM)-stimulated PGI2 formation. However, H2O2 had no effect on phospholipase A2 activity, because ionophore A23187-induced arachidonate release was unimpaired. To determine the effects on cyclooxygenase and PGI2 synthase, prostaglandin products from cells prelabeled with [3H]arachidonate and stimulated with ionophore A23187, or products formed from exogenous arachidonate were examined. Inhibition of cyclooxygenase but not PGI2 synthase was observed. Incubation of H2O2-treated cells with prostaglandin cyclic endoperoxide indicated no inhibition of PGI2 synthase. Thus, in EC low doses of H2O2 potently inhibit cyclooxygenase after brief exposure whereas larger doses and prolonged exposure are required for classical cytolytic effects. Surprisingly, PGI2 synthase, which is known to be extremely sensitive to a variety of lipid peroxides, is not inhibited by H2O2. Lipid solubility, enzyme location within the EC membrane, or the local availability of reducing factors may explain these results, and may be important determinants of the response of EC to oxidative stress.
 ...
PMID:Effect of hydrogen peroxide on prostaglandin production and cellular integrity in cultured porcine aortic endothelial cells. 299 39

A rat aortic explant culture system was developed for the investigation of the effects of hydrocortisone (HC) and the glucocorticoid antagonist, RU486, on prostacyclin (PGI2 synthesis. HC, but not aldosterone, progesterone, 17 beta-estradiol, or testosterone, inhibited spontaneous, epinephrine-stimulated and U46619 (an analog of thromboxane A2)-stimulated PGI2 synthesis by cultured aortic explants in a concentration- and time-dependent manner. Adequate inhibition of aortic explant PGI2 synthesis by physiological concentrations of HC was achieved after an 18-h culture. An 18-h time course was employed in subsequent experiments. In contrast, HC had no effect on arachidonic acid-stimulated PGI2 synthesis. Protein synthesis inhibitors, actinomycin D and cycloheximide, had no effect on the inhibitory action of HC on epinephrine- and U46619-induced release of PGI2. They exerted a direct inhibitory effect on aortic PGI2 synthesis. Arachidonic acid stimulated PGI2 release by the explants and was unaffected either by HC or by treatment with cycloheximide or actinomycin D. RU486 blocked the inhibitory action of HC on aortic PGI2 synthesis in a dose-dependent manner. Thus, the inhibitory effect of HC on vascular PGI2 synthesis is probably mediated through an inhibition of phospholipase A2 and not cyclooxygenase or other PGI2 synthase systems; furthermore, this inhibitory effect is not dependent upon de novo protein synthesis. RU486 antagonizes the inhibitory effect of HC. The inhibition of vascular PGI2 by hydrocortisone has implications in the pathogenesis of steroid-related hypertension and atherosclerosis and the antiinflammatory effect of steroids.
 ...
PMID:Inhibition by hydrocortisone of prostacyclin synthesis by rat aorta and its reversal with RU486. 308 61

We hypothesize that prostacyclin (PGI2) is an anti-atherosclerotic hormone and that atherosclerosis develops when endothelial PGI2 synthetase is inhibited by lipid peroxides. Serum lipid peroxides occur in low-density lipoproteins (LDL). LDL lipid peroxides are elevated in common types of hyperlipoproteinaemias, PGI2 generation is impaired in atherosclerosis, and infusion of synthetic PGI2 into patients alleviates symptoms resulting from arteriosclerosis obliterans, central retinal vein occlusion or spontaneous angina.
 ...
PMID:Prostacyclin and vascular disease. 611 99

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.
 ...
PMID:Inhibition of prostaglandin I2 (PGI2) formation by LDL-cholesterol or LDL-peroxides? 639 33

Prostaglandin biosynthetic activity of miniature-pig aortic endothelial cells was compared with that of smooth muscle cells in culture. When used as homogenates, endothelial cells produced mainly PGE2 and 6-ketoPGF1 alpha (degradated product of PGI2) from arachidonic acid, while they produced a large amount of PGF2 alpha in addition to these when used as intact cells. Intact smooth muscle cells and their homogenates produced PGE2 as a major product. 6-KetoPGF1 alpha was produced by smooth muscle cells in the first few generations and became undetectable after several cultivations. 6-KetoPGF1 alpha and PGE2 were produced by intact or endothelium-depleted aortas. Our results suggest that both endothelial cells and smooth muscle cells in porcine aorta possess PGI2 and PGE2 biosynthetic activities. The subcultivation of smooth muscle cells, but not endothelial cells, in vitro resulted in the rapid disappearance of PGI2 synthetase activity. The PGI2 biosynthetic activity of endothelial cells was several fold higher than that of smooth muscle cells. Porcine smooth muscle cells' low ability to produce PGI2 may offer a reason why atherosclerosis is easily developed in pigs.
 ...
PMID:Comparison of prostaglandin biosynthetic activity between porcine aortic endothelial and smooth muscle cells in culture. 676 17

The present investigation was performed to clarify the effect of EPA on PGI2 production in vitro using cultured rat vascular smooth muscle cells (VSMC). To simulate in vivo conditions, a triacylglycerol (TG) emulsified form of EPA was used. An increase in EPA content was achieved without alteration of arachidonic acid concentration. These experiments clearly demonstrated that co-incubation of EPA-TG increased PGI2 production by cultured VSMC in a dose dependent fashion. Among polyunsaturated fatty acid TG examined (docosahexaenoic acid, linoleic acid, oleic acid and EPA), only EPA-TG was effective. Cyclooxygenase (COX) was activated, but neither phospholipase A2 nor PGI2 synthase activity was changed. EPA treatment did not alter the amount of COX-1 and COX-2 protein in VSMC. Addition of antioxidants, such as butylated hydroxytoluene or vitamin E, decreased MDA levels in the medium and cells and reversed the enhanced PGI2 production in EPA rich-VSMC. Therefore, the high polyunsaturation of EPA could generate low levels of lipid peroxides and thereby lead to activation of COX and an increased PGI2 production. Although EPA increased PGI2 production, only a negligible amount of PGI3 was produced by rat aortic tissues. Enhanced production of PGI2 might contribute to the anti-atherogenic effect of EPA.
Atherosclerosis 1997 Jun
PMID:Mechanisms of enhanced production of PGI2 in cultured rat vascular smooth muscle cells enriched with eicosapentaenoic acid. 919 75

Poor long-term patency and a lack of suitable systemic pharmacologic therapy for the prevention of vein graft failure have prompted the search for effective local gene therapy. Vein grafts are particularly well suited for gene transfer in the clinic because direct access to vein is available during surgical preparation for grafting. In this review, the available animal models are discussed and a new mouse model is highlighted. Recent advances in gene transfer technology are reviewed, including the use of adeno-associated virus and modified adenoviruses that can prolong in vivo transgene expression for months. Gene therapy is intended to reduce early thrombosis, reduce neointima formation, and prevent atherosclerosis in vein grafts. Promising antithrombotic targets include tissue plasminogen activator and thrombomodulin. Nitric oxide synthase, prostacyclin synthase, and tissue inhibitors of metalloproteinases have been used to reduce neointima formation, and vein graft atheroma remains a challenge for the future.
 ...
PMID:Targets for gene therapy of vein grafts. 1057 65

Prostacyclin (PGI(2)) is a potent vasodilator and inhibitor of platelet aggregation that is produced by prostacyclin synthase via the cyclooxygenase (COX) pathway of arachidonic acid metabolism. We investigated the potential role of COX-2 in the production of vasoactive prostanoids by aortic tissue in a rabbit model of dietary cholesterol-induced atherosclerosis. COX-1 was detected as the major isoform by immunoblot analysis in extracts from aortas of normal and 8 week cholesterol-fed animals with COX-2 being induced in atherosclerotic plaques from cholesterol-fed animals. Aortic tissue from cholesterol-fed animals showed decreased levels of basal 6-keto-PGF(1 alpha) and PGE(2) production as compared to the normal controls but showed no difference with respect to their ability to synthesize these prostanoids in response to exogenous arachidonic acid. The highly selective COX-2 inhibitors rofecoxib and the furanone DFP at concentrations of up to 10 micromol/l had no effect on the arachidonic acid-dependent production of 6-keto-PGF(1 alpha), in contrast to indomethacin, which caused a complete inhibition at 0.5 micromol/l. Celecoxib caused a significant inhibition of 6-keto-PGF(1 alpha) at 10 micromol/l but had little effect when the dose was lowered to 1 micromol/l. Similar effects of these inhibitors were observed with respect to the production of PGE(2) and no major difference was observed between aortic tissues from normal and cholesterol-fed animals with regard to inhibitor sensitivity. These results indicate that in a rabbit model of early stage cardiovascular disease, the basal production of 6-keto-PGF(1 alpha) and PGE(2) by aortic tissue is decreased. Furthermore, COX-2 expression is induced in atherosclerotic plaques and may play a role in altering localized synthesis of prostanoids in these lesions but does not appear to significantly impact the arachidonic acid-dependent prostacylin production of aortic tissues, which is largely mediated by COX-1.
Atherosclerosis 2001 Aug
PMID:Effects of COX-2 inhibitors on aortic prostacyclin production in cholesterol-fed rabbits. 1147 39


1 2 Next >>