Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice
| Autor: | Cyrus Tillmann, Zhibing Zhang, Garret A. FitzGerald, Domenico Praticò, Hongwei Li |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Male
medicine.medical_specialty Thromboxane Indomethacin Prostacyclin 6-Ketoprostaglandin F1 alpha Coronary Artery Disease Mice chemistry.chemical_compound Internal medicine medicine Animals Cyclooxygenase Inhibitors Platelet activation Mice Knockout Sulfonamides Multidisciplinary Cyclooxygenase 2 Inhibitors biology Membrane Proteins Biological Sciences Epoprostenol Isoenzymes Mice Inbred C57BL Thromboxane B2 Endocrinology Receptors LDL chemistry Cyclooxygenase 2 Prostaglandin-Endoperoxide Synthases Immunology LDL receptor Cyclooxygenase 1 biology.protein Female lipids (amino acids peptides and proteins) Cyclooxygenase Ex vivo Nimesulide medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences. 98:3358-3363 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.061607398 |
| Popis: | The cyclooxygenase (COX) product, prostacyclin (PGI 2 ), inhibits platelet activation and vascular smooth-muscle cell migration and proliferation. Biochemically selective inhibition of COX-2 reduces PGI 2 biosynthesis substantially in humans. Because deletion of the PGI 2 receptor accelerates atherogenesis in the fat-fed low density lipoprotein receptor knockout mouse, we wished to determine whether selective inhibition of COX-2 would accelerate atherogenesis in this model. To address this hypothesis, we used dosing with nimesulide, which inhibited COX-2 ex vivo , depressed urinary 2,3 dinor 6-keto PGF 1α by approximately 60% but had no effect on thromboxane formation by platelets, which only express COX-1. By contrast, the isoform nonspecific inhibitor, indomethacin, suppressed platelet function and thromboxane formation ex vivo and in vivo , coincident with effects on PGI 2 biosynthesis indistinguishable from nimesulide. Indomethacin reduced the extent of atherosclerosis by 55 ± 4%, whereas nimesulide failed to increase the rate of atherogenesis. Despite their divergent effects on atherogenesis, both drugs depressed two indices of systemic inflammation, soluble intracellular adhesion molecule-1, and monocyte chemoattractant protein-1 to a similar but incomplete degree. Neither drug altered serum lipids and the marked increase in vascular expression of COX-2 during atherogenesis. Accelerated progression of atherosclerosis is unlikely during chronic intake of specific COX-2 inhibitors. Furthermore, evidence that COX-1-derived prostanoids contribute to atherogenesis suggests that controlled evaluation of the effects of nonsteroidal anti-inflammatory drugs and/or aspirin on plaque progression in humans is timely. |
| Databáze: | OpenAIRE |
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