Author: ["Ying Yu","Jinjin Fan","Xin-Sheng Chen","Dairong Wang","Andres J Klein-Szanto","Robert L Campbell","Garret A FitzGerald","Colin D Funk"]
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Abstract
Selective inhibitors of cyclooxygenase-2 (COX2) have attracted widespread media attention because of evidence of an elevated risk of cardiovascular complications in placebo-controlled trials, resulting in the market withdrawal of some members of this class1,2,3,4,5. These drugs block the cyclooxygenase activity of prostaglandin H synthase-2 (PGHS2), but do not affect the associated peroxidase function. They were developed with the rationale of conserving the anti-inflammatory and analgesic actions of traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) while sparing the ability of PGHS1-derived prostaglandins to afford gastric cytoprotection1,2,6. PGHS1 and PGHS2 coexist in the vasculature and in macrophages, and are upregulated together in inflammatory tissues such as rheumatoid synovia7 and atherosclerotic plaque8. They are each believed to function as homodimers6. Here, we developed a new genetic mouse model of selective COX2 inhibition using a gene-targeted point mutation, resulting in a Y385F substitution. Structural modeling and biochemical assays showed the ability of PGHS1 and PGHS2 to heterodimerize and form prostaglandins. The heterodimerization of PGHS1-PGHS2 may explain how the ductus arteriosus closes normally at birth in mice expressing PGHS2 Y385F, but not in PGHS2-null mice9,10.Cite this article
Yu, Y., Fan, J., Chen, XS. et al. Genetic model of selective COX2 inhibition reveals novel heterodimer signaling. Nat Med 12, 699–704 (2006). https://doi.org/10.1038/nm1412 