COX Postulates: Remember the Fibroblast
2023; Lippincott Williams & Wilkins; Volume: 44; Issue: 1 Linguagem: Inglês
10.1161/atvbaha.123.320199
ISSN1524-4636
Autores Tópico(s)Antiplatelet Therapy and Cardiovascular Diseases
ResumoHomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 44, No. 1COX Postulates: Remember the Fibroblast Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBCOX Postulates: Remember the Fibroblast Garret A. FitzGerald Garret A. FitzGeraldGarret A. FitzGerald Correspondence to: Garret A. FitzGerald, MD, 10-116 Smilow Center for Translational Research, 3400 Civic Center Blvd, Building 421, Philadelphia, PA 19104-5158. Email E-mail Address: [email protected] https://orcid.org/0000-0002-5885-6819 Institute for Translational Medicine and Therapeutics, University of Pennsylvania, PA. Originally published16 Nov 2023https://doi.org/10.1161/ATVBAHA.123.320199Arteriosclerosis, Thrombosis, and Vascular Biology. 2024;44:287–289This article is a commentary on the followingWidening the Prostacyclin Paradigm: Tissue Fibroblasts Are a Critical Site of Production and Antithrombotic ProtectionOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: November 16, 2023: Ahead of Print Arachidonic acid is a polyunsaturated fatty acid constituent of cell membranes, mobilized for release by activation of phospholipases by diverse physical and chemical stimuli. Its transformation to unstable endoperoxide prostaglandins G2 and H2 is catalyzed by enzymes (PTGS -1 and 2 [prostaglandin G synthase]) colloquially known as COXs (cyclooxygenases). These lipids, in turn, are transformed to prostaglandins and thromboxane by their respective synthases, expressed such that most cells make one or 2 dominant products. Deletion of the G protein receptors activated by prostaglandins and thromboxane has revealed a remarkably diverse and sometimes contrasting biology.1 The biosynthetic enzymes and receptors in this pathway have proven to be fruitful drug targets. Thus, the clinical efficacy of low dose aspirin is explained by inhibition of platelet COX-1 derived TxA2 (thromboxane A2) and the efficacy of drugs like other NSAIDS (and higher doses of aspirin) by their inhibition of proinflammatory prostaglandins, including PGE2 derived predominantly, but not exclusively from leukocyte COX-2. Expression of both COXs is increased in inflammatory tissues, such as rheumatoid synovia or the atherosclerotic vasculature. As the gastrointestinal adverse effects of nonsteroidal anti-inflammatory drugs had been attributed to inhibition of COX-1 in the gastroduodenal epithelium and platelets, nonsteroidal anti-inflammatory drugs targeting specifically COX-2, like celecoxib and rofecoxib, were developed to widen the therapeutic index.2See accompanying article on page 271Prostaglandins and thromboxane are understood to be evanescent, locally acting lipids. Prostacyclin and TxA2 are rapidly hydrolyzed to 6-keto PGF1α and TxB2, respectively and these, in turn, are further metabolized to chemically stable, but also biologically inactive metabolites. A feature of prostaglandin biology is that the capacity of cells to generate these compounds greatly exceeds actual synthetic rates in vivo. For example, the concentrations of TxB2 in serum of healthy volunteers, reflecting activation of platelet COX-1, is roughly 300 to 400 ng/mL whereas the actual endogenous levels in plasma have been estimated to be 40 years since Bergstrom, Samuelson, and Vane won the Nobel Prize for their discoveries of prostacyclin, TxA2 and the role of the COX enzyme in their formation. Ongoing clinical trials of drugs targeting prostaglandin receptors are investigating their importance in settings as diverse as cancer immunotherapy and epilepsy. The discoveries of Kariko and Weissman, celebrated in this year's Nobel, afford the promise of tissue specific delivery of RNA that might, in the future, exploit this therapeutically rich pathway with even greater precision.ARTICLE INFORMATIONDisclosures None.FootnotesFor Disclosures, see page 289.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to: Garret A. 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Thromboxane-prostanoid receptor signaling drives persistent fibroblast activation in pulmonary fibrosis.Am J Respir Crit Care Med. 2022; 206:596–607. doi: 10.1164/rccm.202106-1503OCCrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesWidening the Prostacyclin Paradigm: Tissue Fibroblasts Are a Critical Site of Production and Antithrombotic ProtectionMaria Vinokurova, et al. Arteriosclerosis, Thrombosis, and Vascular Biology. 2024;44:271-286 January 2024Vol 44, Issue 1 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.123.320199PMID: 37970715 Originally publishedNovember 16, 2023 KeywordsEditorialsaspirincell membraneprostaglandinrofecoxibPDF download Advertisement
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