Regulation of Thrombomodulin Expression in Human Vascular Smooth Muscle Cells by COX-2–Derived Prostaglandins

Rabausch, Kerstin; Bretschneider, Ellen; Sarbia, Mario; Meyer-Kirchrath, Jutta; Censarek, Petra; Pape, R. De; Fischer, Jens W.; Schrör, Karsten; Weber, Artur‐Aron

doi:10.1161/01.res.0000153150.27690.f2

Cited by 76 publications

(63 citation statements)

References 34 publications

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“…The basic literature is replete with recent studies demonstrating that genomic or pharmacological removal of prostacyclin leads to both platelet-dependent [13][14][15] and plateletindependent 16 mechanisms for induction of thrombosis, plaque destabilization, or atherogenesis. In addition, COX-2 is recognized as a key source of prostacyclin under normal laminar flow conditions in the vasculature and has been shown to be cardioprotective in ischemia-reperfusion injury.…”

Section: Pharmacology Of Cox Inhibitionmentioning

confidence: 99%

Cardiovascular Effects of the Cyclooxygenase Inhibitors

White

2007

Hypertension

106

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C yclooxyenase (COX)-2 selective inhibitors were developed to create a new class of nonsteroidal antiinflammatory drugs (NSAIDs) with properties similar to those of nonselective NSAIDS but without their potential COX-1-mediated gastrointestinal toxicities. 1,2 Studies of the various COX-2 selective inhibitors have shown that they are in fact associated with a significantly lower risk of upper and lower gastrointestinal complications than traditional NSAIDs, except in patients who are taking concomitant low-doses of aspirin.Recent evidence also suggests that some doses of the COX-2 selective inhibitors, and perhaps some traditional NSAIDs as well, are associated with an increased risk of adverse cardiovascular (CV) events. Reports of a higher incidence of myocardial infarction (MI) among patients with arthritis taking high doses of the COX-2 selective inhibitor rofecoxib compared with those taking the NSAID naproxen 2-4 have had heightened concerns since 2001 regarding selective COX-2 inhibitor safety. In addition, in early 2005, elevated CV event rates were reported in patients with spontaneous adenomatous polyps who were taking high doses of celecoxib compared with placebo 5 and in patients who received parenteral parecoxib followed by oral valdecoxib versus placebo immediately after coronary artery bypass graft surgery. 6 This article represents a compilation of the data concerning the effects of both nonselective and selective NSAIDs on blood pressure (BP), particularly in patients with hypertension and/or on antihypertensive agents. Subsequently, the impact that the COX inhibitors have on CV events from several recent clinical trials for the treatment of arthritis or for cancer prevention, as well as from selected large observational studies, is discussed. CV Pharmacology of COX InhibitionCOXs participate in numerous physiological functions and human pathological disorders. The COX-1 isoform is constitutively expressed in most tissues where it regulates the synthesis of prostaglandins. COX-1 is the only form of the enzyme in mature platelets and is also expressed in the vascular endothelium, the gastrointestinal epithelium, brain, spinal cord, and kidney. The COX-2 isoform plays an important role in induction of inflammation in response to injury, as well as later repair of inflammation. It is noteworthy that COX-2 may be induced by bacterial endotoxins, cytokines, and growth factors and is expressed in atherosclerotic plaques, during angiogenesis, during wound healing, and in a variety of epithelial cell cancers. [7][8][9] In addition, COX-2 is constitutively expressed in the macula densa and renal medullary interstitium. 10,11 As discussed below, one result of COX-2 inhibition is a reduction in natriuresis and the development of hypertension in susceptible populations. The COX isoenzymes are similar in structure, but the substrate-binding channel of COX-2 contains a side pocket that is absent in COX-1. This structural difference has allowed for the design and development of COX inhibitors with side chains ...

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Section: Pharmacology Of Cox Inhibitionmentioning

confidence: 99%

Cardiovascular Effects of the Cyclooxygenase Inhibitors

White

2007

Hypertension

106

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“…1 cAMP triggers a host of cellular responses including inhibition of platelet aggregation, promotion of vascular smooth muscle cell relaxation, and induction of thrombomodulin, an important inhibitor of blood coagulation. 22,23 Recently, it has been reported an antioxidant role for PGI 2 through the induction of heme oxygenase (HO)-1. 24 HO-1 (32-kDa stress-inducible protein) catalyzes the degradation of heme to liberate free iron, carbon monoxide (CO) and biliverdin in mammalian cells.…”

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confidence: 99%

Induction of Prostacyclin by Steady Laminar Shear Stress Suppresses Tumor Necrosis Factor-α Biosynthesis via Heme Oxygenase-1 in Human Endothelial Cells

Francesco

Totani

Dovizio

et al. 2009

Circulation Research

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Abstract-Cyclooxygenase (COX)-2 is among the endothelial genes upregulated by uniform laminar shear stress (LSS), characteristically associated with atherosclerotic lesion-protected areas. We have addressed whether the induction of COX-2-dependent prostanoids in endothelial cells by LSS plays a role in restraining endothelial tumor necrosis factor (TNF)-␣ generation, a proatherogenic cytokine, through the induction of heme oxygenase-1 (HO)-1, an antioxidant enzyme. In human umbilical vein endothelial cells (HUVECs) exposed to steady LSS of 10 dyn/cm 2 for 6 hours, COX-2 protein was significantly induced, whereas COX-1 and the downstream synthases were not significantly modulated. This was associated with significant (PϽ0.05) increase of 6-keto-prostaglandin (PG)F 1␣ (the hydrolysis product of prostacyclin), PGE 2 , and PGD 2 . In contrast, TNF-␣ released in the medium in 6 hours (3633Ϯ882 pg) or detected in cells lysates (1091Ϯ270 pg) was significantly (PϽ0.05) reduced versus static condition (9100Ϯ2158 and 2208Ϯ300 pg, respectively). Coincident induction of HO-1 was detected. The finding that LSS-dependent reduction of TNF-␣ generation and HO-1 induction were abrogated by the selective inhibitor of COX-2 NS-398, the nonselective COX inhibitor aspirin, or the specific prostacyclin receptor (IP) antagonist RO3244794 illuminates the central role played by LSS-induced COX-2-dependent prostacyclin in restraining endothelial inflammation. Carbacyclin, an agonist of IP, induced HO-1. Similarly to inhibition of prostacyclin biosynthesis or activity, the novel imidazole-based HO-1 inhibitor QC15 reversed TNF-␣ reduction by LSS. These findings suggest that inhibition of COX-2-dependent prostacyclin might contribute to acceleration of atherogenesis in patients taking traditional nonsteroidal antiinflammatory drugs (NSAIDs) and NSAIDs selective for COX-2 through downregulation of HO-1, which halts TNF-␣ generation in human endothelial cells. Key Words: cyclooxygenase Ⅲ endothelial cells Ⅲ prostaglandins Ⅲ prostanoids Ⅲ shear stress Ⅲ tumor necrosis factor-␣ P rostanoids, including prostaglandin (PG)E 2 , PGF 2␣ , PGD 2 , prostacyclin (PGI 2 ), and thromboxane (TX)A 2 , are lipid autacoids, immediately released outside the cell after intracellular biosynthesis, that modulate a wide variety of physiological and pathological processes. 1 They are generated by 3 sequential enzymatic steps involving: (1) phospholipase A 2 enzymes, (2) cyclooxygenase (COX) enzymes (ie, COX-1 and COX-2), 2 and (3) [3][4][5][6][7][8][9] Two isoforms of COX (COX-1 and COX-2) have been cloned and characterized. 2 COX-1 is considered a "housekeeping gene" by virtue of constitutive low levels of expression in most cell types.Differently, the gene for COX-2 is a primary response gene with many regulatory sites; thus, COX-2 expression can be rapidly induced by bacterial endotoxin (lipopolysaccharide), cytokines, such as interleukin (IL)-1␤, and tumor necrosis factor (TNF)-␣, growth factors, and tumor promoter phorbol myristate acetate. 10 However, COX-2...

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“…The use of drugs that interfere with the production of cyclooxygenase-2-derived eicosanoids (i.e., coxibs, tNSAIDs, and glucocorticoids) appears to affect the production of prostacyclin (22)(23)(24)(25) and thus shifts the balance between cardioprotective and prothrombotic prostanoids (26,27 ). Our finding that increased CVAEs occurred only in patients with NT-proBNP values Ն100 ng/L is most likely related to this balance.…”

Section: Discussionmentioning

confidence: 66%