Regulation of Cyclooxygenase Synthesis in Vascular Smooth Muscle Cells by Epidermal Growth Factor

Bailey, J. Martyn; Hla, Timothy; Muza, Barbara; Pash, James M.

doi:10.1007/978-1-4684-4946-4_15

Cited by 24 publications

(28 citation statements)

References 9 publications

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“…In cultures of smooth muscle cells (16) or endothelial cells (17), the inhibitory effects of aspirin on cyclooxygenase are transient, and prostaglandin production recovers within [2][3][4][5] hr. This recovery is due to new enzyme synthesis (17).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of aspirin and salicylate in relation to inhibition of arachidonate cyclooxygenase and antiinflammatory activity.

Higgs¹,

Salmon²,

Henderson³

et al. 1987

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

201

109

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Among the nonsteroid antiinflammatory drugs there is generally a close correlation between the potency of their inhibition of arachidonate cyclooxygenase, and thus prostaglandin production, and their antiinflammatory activity.One anomaly in this generalization is that whereas aspirin and salicylate are equipotent as antiinflammatory agents, salicylate is less active than aspirin in inhibiting prostaglandin production in vitro. Using rats, we have now measured the concentrations of aspirin and salicylate in plasma and in inflammatory exudates after their oral administration and determined their effects on thromboxane B2 production in clotting blood and prostaglandin (PG) E2 concentrations in the exudates. We have also investigated the effects of both drugs, at concentrations achieved in the exudates, on PGE2 production by nonproliferative explants of acutely inflamed tissues. Aspirin is rapidly metabolized, resulting in peak concentrations of salicylate in the plasma and exudate that exceeded peak concentrations of aspirin by 30-to 50-fold. Furthermore, concentrations of aspirin rapidly declined, whereas high concentrations of salicylate persisted in the plasma and in the exudate for up to 6 hr after a single administration of aspirin. Both drugs reduced PGE2 concentrations in inflammatory exudates by 50-70%, but aspirin was considerably more potent than salicylate in inhibiting thromboxane B2 production in clotting blood. The concentration of salicylate found in inflammatory exudates 6 hr after the administration of aspirin was sufficient to reduce PGE2 production in explants by more than 50%. We conclude that the antiinflammatory action of both drugs depends on the inhibition of PGE2 synthesis by salicylate.The discovery that aspirin, indomethacin, and salicylate inhibit the synthesis of prostaglandins (1-3) provided the first comprehensive explanation of the mechanism of action of these drugs. Subsequent studies have shown that the broad group of nonsteroid antiinflammatory drugs inhibits arachidonate cyclooxygenase, the enzyme that converts arachidonic acid to prostaglandin endoperoxides (for review see ref. 4). However, anomalies exist in the potencies of these drugs with respect to their antiinflammatory activities and to their ability to inhibit cyclooxygenase; of particular interest has been the disparity between the potency of aspirin and salicylate in inhibiting cyclooxygenase. Aspirin and salicylate are equipotent as antiinflammatory agents, but aspirin is some 20 times more potent than salicylate in inhibiting an enzyme preparation from guinea pig lung in vitro (1). Furthermore, it has been reported that oral administration of aspirin (10 mg/kg) inhibited thromboxane (TX) production by rat platelets but 20 times this dose of salicylate had no effect (5). These findings led to speculation that the antiinflammatory activity of these drugs was not related to inhibition of prostaglandin (PG) synthesis (5, 6).We have now (i) measured the concentrations of aspirin and salicylate in plasma and inflam...

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of aspirin and salicylate in relation to inhibition of arachidonate cyclooxygenase and antiinflammatory activity.

Higgs¹,

Salmon²,

Henderson³

et al. 1987

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

201

109

View full text Add to dashboard Cite

show abstract

“…In the following years, a number of studies have illustrated that COX activity is increased in certain inflammatory states and is induced in cells by proinflammatory cytokines and growth factors in vitro (Bailey et al, 1985;Sano et al, 1992). Needleman and his group continued their earlier work and reported that bacterial lipopolysaccharide (LPS) increased the synthesis of PGs in human monocytes in vitro and in mouse peritoneal macrophages in vivo.…”

Section: The Prostaglandin Biosynthetic Pathwaymentioning

confidence: 99%

Modulation of Prostaglandin Biosynthesis by Nitric Oxide and Nitric Oxide Donors

Muscoli²,

et al. 2005

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“…The rate-limiting step in the prostanoid synthesis pathway is catalyzed by the integral membrane protein cyclooxygenase (COX), also known as prostaglandin H 2 (PGH 2 ) synthase [2,3], which is localized to the endoplasmic reticulum (ER) and nuclear envelope [4]. COX is bifunctional, converting arachidonic acid (AA), an omega-6 fatty acid, to the precursor prostaglandin G 2 (PGG 2 ) and subsequently converting PGG 2 to the precursor PGH 2 via cyclooxygenase and peroxidase activities, respectively.…”

Section: Introductionmentioning

confidence: 99%

Glycosylation regulates turnover of cyclooxygenase‐2

Sevigny

Alas

et al. 2006

FEBS Letters

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Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step in the prostanoid biosynthesis pathway, converting arachidonic acid into prostaglandin H 2 . COX-2 exists as 72 and 74 kDa glycoforms, the latter resulting from an additional oligosaccharide chain at residue Asn 580 . In this study, Asn 580 was mutated to determine the biological significance of this variable glycosylation. COS-1 cells transfected with the mutant gene were unable to express the 74 kDa glycoform and were found to accumulate more COX-2 protein and have five times greater COX-2 activity than cells expressing both glycoforms. Thus, COX-2 turnover appears to depend upon glycosylation of the 72 kDa glycoform. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.

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Regulation of Cyclooxygenase Synthesis in Vascular Smooth Muscle Cells by Epidermal Growth Factor

Cited by 24 publications

References 9 publications

Pharmacokinetics of aspirin and salicylate in relation to inhibition of arachidonate cyclooxygenase and antiinflammatory activity.

Pharmacokinetics of aspirin and salicylate in relation to inhibition of arachidonate cyclooxygenase and antiinflammatory activity.

Modulation of Prostaglandin Biosynthesis by Nitric Oxide and Nitric Oxide Donors

Glycosylation regulates turnover of cyclooxygenase‐2

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