COX-2–Derived Prostacyclin Modulates Vascular Remodeling

Rudic, R. Daniel; Brinster, Derek R.; Cheng, Yan; Fries, Susanne; Song, Wen‐Liang; Austin, Sandra; Coffman, Thomas M.; FitzGerald, Garret A.

doi:10.1161/01.res.0000170888.11669.28

Cited by 103 publications

(88 citation statements)

References 54 publications

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“…The observed reduction in blood flow in IP À/À mice may, however, have an additional explanation. It was recently shown that IP À/À mice display an increased proliferative response and decreased luminal area weeks after vascular injury (Cheng et al, 2002;Rudic et al, 2005), and we cannot exclude that the decreased blood flow 24 h after trauma may, in part, be explained by such an effect.…”

Section: Discussionmentioning

confidence: 87%

Increased Cortical Cell Loss and Prolonged Hemodynamic Depression after Traumatic Brain Injury in Mice Lacking the IP Receptor for Prostacyclin

Lundblad

Grände

Bentzer

2007

J Cereb Blood Flow Metab

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Prostacyclin is the major arachidonic acid metabolite of the vascular endothelium and is produced mainly via the cyclooxygenase-2 pathway. By acting on the prostacyclin (IP) receptor on platelets and vascular smooth muscle cells, prostacyclin exerts vasodilatory and antiaggregative/antiadhesive effects. Previous studies have shown that prostacyclin production increases after brain trauma, but the importance of prostacyclin for posttraumatic hemodynamic alterations and neuron survival has not been investigated. This study evaluated if endogenous prostacyclin plays a role in the pathophysiologic process in the brain after brain trauma. This was performed by comparing prostacyclin (IP) receptor-deficient (IP À/À ) mice and mice with functional IP receptor (IP + / + ) after a controlled cortical injury regarding contusion volume, cerebral blood flow ([ 14 C]iodoantipyrine autoradiography), number of perfused capillaries (fluorescein isothiocyanate-dextran fluorescence technique), the transfer constant (K i ) for [51 Cr]EDTA, and brain water content (wet vs dry weight) in the injured and contralateral cortex. Contusion volume was increased in IP À/À mice compared with IP + / + mice. Three hours after trauma, cortical blood flow was decreased in the injured cortex of both groups and the reduction in blood flow in the cortex of the IP À/À mice persisted from 3 to 24 h, whereas blood flow approached normal values in the IP + / + mice after 24 h. No differences could be detected between the two genotypes regarding other hemodynamic parameters. We conclude that the prostacyclin IP receptor is beneficial for neuron survival after brain trauma in mice, an effect that may be mediated by improved cortical perfusion.

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Section: Discussionmentioning

confidence: 87%

Increased Cortical Cell Loss and Prolonged Hemodynamic Depression after Traumatic Brain Injury in Mice Lacking the IP Receptor for Prostacyclin

Lundblad

Grände

Bentzer

2007

J Cereb Blood Flow Metab

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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

103

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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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“…Mechanistically, this is attributable to suppression of COX-2-derived prostacyclin (PGI 2 ; ref. 6), which acts as a general restraint on endogenous stimuli, including platelet COX-1-derived thromboxane (Tx) A 2 , to platelet activation, vascular proliferation and remodeling, hypertension, atherogenesis, and cardiac function (7)(8)(9)(10)(11)(12)(13). Precise estimates of the incidence of this risk are not available.…”

mentioning

confidence: 99%

Deletion of microsomal prostaglandin E synthase-1 augments prostacyclin and retards atherogenesis

Wang

Zukas

Hui

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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184

165

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Prostaglandin (PG) E2 is formed from PGH2 by a series of PGE synthase (PGES) enzymes. Microsomal PGES-1 ؊/؊ (mPGES-1 ؊/؊ ) mice were crossed into low-density lipoprotein receptor knockout (LDLR ؊/؊ ) mice to generate mPGES-1 ؊/؊ LDLR ؊/؊ s. Urinary 11␣-hydroxy-9, 15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M) was depressed by mPGES-1 deletion. Vascular mPGES-1 was augmented during atherogenesis in LDLR ؊/؊ s. Deletion of mPGES-1 reduced plaque burden in fat-fed LDLR ؊/؊ s but did not alter blood pressure. mPGES-1 ؊/؊ LDLR ؊/؊ plaques were enriched with fibrillar collagens relative to LDLR ؊/؊ , which also contained small and intermediate-sized collagens. Macrophage foam cells were depleted in mPGES-1 ؊/؊ LDLR ؊/؊ lesions, whereas the total areas rich in vascular smooth muscle cell (VSMC) and matrix were unaltered. mPGES-1 deletion augmented expression of both prostacyclin (PGI 2) and thromboxane (Tx) synthases in endothelial cells, and VSMCs expressing PGI synthase were enriched in mPGES-1 ؊/؊ LDLR ؊/؊ lesions. Stimulation of mPGES-1 ؊/؊ VSMC and macrophages with bacterial LPS increased PGI 2 and thromboxane A2 to varied extents. Urinary PGE-M was depressed, whereas urinary 2,3-dinor 6-keto PGF 1␣, but not 2,3-dinor-TxB2, was increased in mPGES-1 ؊/؊ LDLR ؊/؊ s. mPGES-1-derived PGE2 accelerates atherogenesis in LDLR ؊/؊ mice. Disruption of this enzyme retards atherogenesis, without an attendant impact on blood pressure. This may reflect, in part, rediversion of accumulated PGH 2 to augment formation of PGI 2. Inhibitors of mPGES-1 may be less likely than those selective for cyclooxygenase 2 to result in cardiovascular complications because of a divergent impact on the biosynthesis of PGI 2.atherosclerosis ͉ cyclooxygenase ͉ macrophage ͉ vascular smooth muscle cell R ecent placebo-controlled trials have revealed that nonsteroidal antiinflammatory drugs (NSAIDs) selective for inhibition of cyclooxygenase 2 (COX-2) confer a small but absolute risk of myocardial infarction and stroke (1-5). Mechanistically, this is attributable to suppression of COX-2-derived prostacyclin (PGI 2 ; ref. 6), which acts as a general restraint on endogenous stimuli, including platelet COX-1-derived thromboxane (Tx) A 2 , to platelet activation, vascular proliferation and remodeling, hypertension, atherogenesis, and cardiac function (7-13). Precise estimates of the incidence of this risk are not available. However, the relative risk is small and likely to be conditioned by such factors as drug exposure, underlying cardiovascular risk of the patients exposed and concomitant therapies (6, 13). However, the consumption of celecoxib, rofecoxib, and valdecoxib by millions has raised concern that many patients may have suffered cardiovascular adverse events from these drugs.Inhibitors of COX-2 afford relief from pain and inflammation principally by suppressing prostaglandin (PG) E 2 and PGI 2 . Deletion and͞or antagonism of receptors for both of these PGs modulate the response to both painful and inflammatory stimuli (14-17). Altho...

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COX-2–Derived Prostacyclin Modulates Vascular Remodeling

Cited by 103 publications

References 54 publications

Increased Cortical Cell Loss and Prolonged Hemodynamic Depression after Traumatic Brain Injury in Mice Lacking the IP Receptor for Prostacyclin

Increased Cortical Cell Loss and Prolonged Hemodynamic Depression after Traumatic Brain Injury in Mice Lacking the IP Receptor for Prostacyclin

Cardiovascular Effects of the Cyclooxygenase Inhibitors

Deletion of microsomal prostaglandin E synthase-1 augments prostacyclin and retards atherogenesis

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