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)

There is a close inter-relationship between oxidative stress, coagulation, inflammation, and smooth muscle cell growth as key components of atherosclerosis (Fig. 1). As an analgesic and anti-pyretic, aspirin has been in use for over a century. It acetylates the COX enzyme, irreversibly inhibiting the formation of prostaglandin. Its action on platelet TxA2 has highlighted its role as an anti-thrombotic agent in cardiovascular patients. Over the last two decades, unique anti-inflammatory properties of aspirin not shared by other non-steroidals have been discovered. Aspirin biotransforms into salicylate, which has diverse but potent anti-inflammatory properties. As we strive to better understand the concepts of atherogenesis, chronic inflammation, oxidative stress, and endothelial activation, these novel effects of aspirin provide new insights as to how this wonder drug works. These effects of aspirin alter many, if not all, components of the atherogenesis cascade shown in Fig. 1.
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PMID:Relevance of platelet-independent effects of aspirin to its salutary effect in atherosclerosis-related events. 1614 21

Conjugated linoleic acid (CLA) refers to a group of positional and geometric isomers of linoleic acid and has been shown to suppress the development of atherosclerosis in experimental models. However, the mechanism involved is unclear although it is believed it may act as a cyclooxygenase inhibitor or as an agonist of the nuclear receptors, peroxisome proliferator activated receptors (PPARs). In this study, we examined the effect of cis-9,trans-11:trans-10,cis-12-CLA (80:20 blend) on the regression of pre-established atherosclerosis. ApoE(-/-) mice fed a 1% cholesterol diet were randomized at 8 weeks to continue receiving the diet supplemented with 1% control saturated fat or 1% CLA blend for a further 8 weeks. CLA supplementation did not simply prevent progression but induced almost complete resolution of atherosclerosis. Although CLA inhibited platelet deposition, as detected by staining of platelet glycoprotein alpha11b beta111a, it did not inhibit COX-mediated generation of prostaglandins in this model. However, PPARalpha and PPARgamma expression was increased in the aorta of the CLA-treated animals. This was coincident with decreased macrophage accumulation and decreased expression of the macrophage scavenger receptor CD36 and increased apoptosis in the aorta in vivo. CLA induces the resolution of atherosclerosis by negatively regulating the expression of pro-inflammatory genes and inducing apoptosis in the atherosclerotic lesion.
Atherosclerosis 2006 Jul
PMID:Profound resolution of early atherosclerosis with conjugated linoleic acid. 1618

Platelets are rich sources of growth factors and enzymes that are implicated in a number of diseases including obesity, atherosclerosis, heart disease, syndrome X, liver and kidney diseases and certain types of cancers. In this research we investigated, if platelets in Zucker obese rats differ from their lean counterparts with respect to the levels of TGF-beta and COX isoforms, implicated in the pathogenesis of chronic diseases. In addition, we investigated if energy intake of the animals affects the platelet physiology. Platelets were isolated from obese and lean rats bearing preneoplastic lesions in their colon. Prior to platelet isolation these rats were fed either ad libitum (Ob or Ln) or energy restricted (Ob-ER or Ln-ER) diets for 8 weeks (n = 8/group). The levels of TGF-beta1/-beta2 and COX-1/-2 proteins in platelets were analyzed by Western blot. The platelets of the Ob rats had significantly higher levels of TGF-beta1, COX-1/-2 (p < 0.001) than did the platelets of the Ln rats and were not affected by moderate energy restriction. There were no significant differences in the protein expression of platelet TGF-beta2 among any of the groups. These results demonstrate that cytokines and candidates playing a role in the pathogenesis of chronic diseases, such as TGF-beta1 and COX-1/-2, are over-expressed in platelets of Zucker obese rats by comparison to their lean counterparts. These findings also demonstrate that the genotype of the animals exerts a significant effect on the biochemical composition of the platelets and could contribute to the pathogenesis of colon cancer and other metabolic abnormalities associated with obesity.
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PMID:Obese state leads to elevated levels of TGF-beta and COX isoforms in platelets of Zucker rats. 1647 87

Aspirin, a standard non-steroidal anti-inflammatory drug (NSAID) is currently used in antithrombotic treatment. However, its use is limited by largely recognized gastrotoxicity and recommended doses are low. The major side effect of aspirin is related to its ability to suppress prostaglandin (PG) synthesis by constitutive cyclooxygenase-1 (COX-1). Specific inhibitors of COX-2, the inducible isoform of COX which was more recently described, have potent antiinflammatory effects. They are associated with minor risk of gastric tractus toxicity and reduced inflammatory leukocyte components known for their proatherothrombotic properties. Nevertheless, recent findings attributed a significant cardiovascular risk to some of them. 5-lipoxygenase (5-LOX), an enzyme mainly expressed by leukocytes, is responsible for the generation of leukotrienes, the major lipidic proinflammatory mediators. Development of combined inhibitors of 5-LOX and COX isoforms 1 and 2 inaugurate an interesting new therapeutic pathway. Indeed, such inhibitors suppress not only the activation of platelets, leukocytes and endothelial cells but also prevent their metabolic and functional interactions. In addition to their broad spectrum inhibition, they may be associated with the minor gastrotoxic effect. Thus, platelet-leukocyte interactions which dominate the underlying inflammatory process particularly in atherosclerosis, might reinforce the benefits of such inhibitors.
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PMID:[Prevention of thrombosis and vascular inflammation: importance of combined cyclooxygenase and 5-lipoxygenase inhibitors]. 1660 25

The inducible isoform of cyclooxygenase-2 (COX-2) plays a role in pathophysiologic processes like inflammation and pain but is also constitutively expressed in tissues such as the kidney or vascular endothelium, where it exerts important physiologic functions. Although much evidence exists that implicates COX-2 in atherosclerosis, its role in this setting remains substantially uncertain. This observation is also confirmed by the results of clinical trials of selective COX-2 inhibitors. Treatment with these drugs, developed with the assumption that they would be as effective as nonselective COX inhibitors but without their gastrointestinal side effects, has been reported to be associated with an increased cardiovascular risk. In this article, we review the pattern of expression of COX-2 in the cellular players of atherothrombosis, its role as a determinant of plaque vulnerability, and the vascular effects on prostanoid inhibition by COX-2 inhibitors.
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PMID:Cyclooxygenase-2 inhibition: vascular inflammation and cardiovascular risk. 1664 Sep 62

Scavenger receptor class B type I (SR-BI) has been shown to be expressed in human atherosclerotic plaque macrophages, where it is believed to reduce atherosclerosis by promoting cholesterol efflux. In this study we investigated the influence of aspirin and other NSAIDs on SR-BI expression and function in cultured human macrophages as well as in different mouse strains. Incubation of human macrophages with 0.5 mmol/l aspirin resulted in increased SR-BI protein expression and increased uptake of HDL-associated [3H]cholesteryl oleate without changes of SR-BI mRNA levels. In contrast, using 5 mmol/l of aspirin, SR-BI expression and function were significantly decreased. Sodium salicylate exerted similar effects on SR-BI expression, whereas no effects were observed using known COX1/2 inhibitors ibuprofen and naproxen, respectively. In in vivo studies low-dose aspirin treatment (6 mg/kg.day) induced SR-BI expression in wild-type and PPAR-alpha knockout mice, respectively, whereas the opposite effect was observed upon high-dose aspirin treatment (60 mg/kg.day) in these animals. We could show that COX-independent effects of aspirin were able to enhance expression of SR-BI in macrophages in a post-transcriptional, PPAR-alpha independent way, suggesting a novel pharmacologic effect of aspirin.
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PMID:Aspirin regulates expression and function of scavenger receptor-BI in macrophages: studies in primary human macrophages and in mice. 1681 7

Nitric oxide (*NO) and eicosanoids are critical mediators of physiological and pathophysiological processes. They include inflammation and atherosclerosis. *NO production and eicosanoid synthesis become disrupted during atherosclerosis and thus, it is important to understand the mechanisms that may contribute to this outcome. We, and others, have shown that nitrogen oxide (NO(x)) species modulate cyclooxygenase (COX; also known as prostaglandin H(2) synthase) activity and alter eicosanoid production. We have determined that peroxynitrite (ONOO(-)) has multiple effects on COX activity. ONOO(-) can provide the peroxide tone necessary for COX activation, such that simultaneous exposure of COX to its arachidonic acid substrate and ONOO(-) results in increased eicosanoid production. Alternatively, in the absence of arachidonic acid, ONOO(-) can modify COX through nitration of an essential tyrosine residue (Tyr385) such that it is incapable of catalysis. In this regard, we have shown that COX nitration occurs in human atherosclerotic tissue and in aortic lesions from ApoE(-/-) mice kept on a high fat diet. Additionally, we have demonstrated that Tyr nitration in ApoE(-/-) mice is dependent on the inducible form of NO synthase (iNOS). Under conditions where ONOO(-) persists and arachidonic acid is not immediately available, the cell may try to correct the situation by responding to ONOO(-) and releasing arachidonic acid via a signaling pathway to favor COX activation. Other post-translational modifications of COX by NO(x) species include S-nitrosation of cysteine (Cys) residues (which may have an activating effect) and Cys oxidation. The central focus of this review will include a discussion of how NO(x) species alter COX activity at the molecular level and how these modifications may contribute to altered eicosanoid output during atherosclerosis and lesion development.
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PMID:Oxidative alterations of cyclooxygenase during atherogenesis. 1684 82

Nitric oxide (*NO) and eicosanoids are critical mediators of physiological and pathophysiological processes. They include inflammation and atherosclerosis. *NO production and eicosanoid synthesis become disrupted during atherosclerosis and thus, it is important to understand the mechanisms that may contribute to this outcome. We, and others, have shown that nitrogen oxide (NOx) species modulate cyclooxygenase (COX; also known as prostaglandin H2 synthase) activity and alter eicosanoid production. We have determined that peroxynitrite (ONOO-) has multiple effects on COX activity. ONOO- can provide the peroxide tone necessary for COX activation, such that simultaneous exposure of COX to its arachidonic acid substrate and ONOO- results in increased eicosanoid production. Alternatively, in the absence of arachidonic acid, ONOO- can modify COX through nitration of an essential tyrosine residue (Tyr385) such that it is incapable of catalysis. In this regard, we have shown that COX nitration occurs in human atherosclerotic tissue and in aortic lesions from ApoE-/- mice kept on a high fat diet. Additionally, we have demonstrated that Tyr nitration in ApoE-/- mice is dependent on the inducible form of NO synthase (iNOS). Under conditions where ONOO- persists and arachidonic acid is not immediately available, the cell may try to correct the situation by responding to ONOO- and releasing arachidonic acid via a signaling pathway to favor COX activation. Other post-translational modifications of COX by NOx species include S-nitrosation of cysteine (Cys) residues (which may have an activating effect) and Cys oxidation. The central focus of this review will include a discussion of how NOx species alter COX activity at the molecular level and how these modifications may contribute to altered eicosanoid output during atherosclerosis and lesion development.
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PMID:Reprint of "oxidative alterations of cyclooxygenase during atherogenesis" [Prostag. Oth. Lipid. M. 80 (2006) 1-14]. 1716 26

Despite initial promising reports that anti-inflammatory properties of cycloxygenase-2 (COX-2) inhibitors may confer anti-atherosclerosis effects and stabilize the atherosclerotic plaque, subsequent data from long-term clinical trials have shown that selective COX-2 inhibitors are associated with increased risk of cardiovascular events. The commonly cited explanation is that selective inhibition of COX-2 leads to depletion of prostacyclin, whereas the production of pro-thrombotic thromboxane by means of cycloxygenase-1 (COX-1) is unopposed. This hypothesis seems unlikely as the overall explanation, because low-dose aspirin does not decrease the increased risk associated with COX-2 inhibitors. Moreover, the risk associated with nonselective COX inhibitors may be similar to selective COX-2 inhibitors. Alternative hypotheses include (1) elevated blood pressure, (2) abnormal vascular remodeling, (3) inhibition of protective mechanisms against ischemia-reperfusion injury, and (4) inhibition of 15-epi-lipoxin production. Varying results in different experimental models may be related to the fact that COX-2 is involved in numerous cellular functions. Inhibiting COX-2 in inflammatory cells may have favorable effects, whereas in organs such as the heart and brain and/or blood vessels may have deleterious effects. Currently, the "selective COX-2 inhibitors" are not selective in the sense that they inhibit COX-2 in all tissues without predilection to inflammatory cells and, as a result, may summate to increase the risk of cardiovascular events.
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PMID:The cycloxygenase 2 (COX-2) story: it's time to explain, not inflame. 1756 80

Atherosclerosis is a disorder of lipid metabolism as well as a chronic inflammatory disease. Cyclooxygenase-2 (COX-2), an inducible isoform responsible for high levels of prostaglandin production during inflammation and immune responses, mediates a variety of biological actions involved in vascular pathophysiology. We have previously shown that COX-2 gene expression is dramatically induced by a lipid-derived endogenous electrophile, 4-hydroxy-2-nonenal (HNE) (Kumagai, T., Matsukawa, N., Kaneko, Y., Kusumi, Y., Mitsumata, M., and Uchida, K. (2004) J. Biol. Chem. 279, 48389-48396). In the present study, based on the finding that HNE induced COX-2 expression only in the serum-containing media, we characterized a serum component essential for the HNE-induced COX-2 induction and found that low density lipoprotein (LDL) that had been denatured by freeze-thawing or oxidized LDL might be involved in the COX-2 induction. Moreover, we characterized the cellular events triggered by the combined stimulus of HNE and oxidized LDL and established that COX-2 induction is regulated by two sets of signaling mechanisms, one for the up-regulation of the scavenger receptor CD36 by HNE and one for the CD36-mediated COX induction by oxidized LDL. These findings represent a demonstration of a link between lipoprotein modification and activation of the inflammatory potential of macrophages.
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PMID:Identification of a serum component that regulates cyclooxygenase-2 gene expression in cooperation with 4-hydroxy-2-nonenal. 1758 12


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