{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2023,10,13]],"date-time":"2023-10-13T06:10:45Z","timestamp":1697177445949},"reference-count":47,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2009,1,29]],"date-time":"2009-01-29T00:00:00Z","timestamp":1233187200000},"content-version":"vor","delay-in-days":303,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2008,4]]},"abstract":"<jats:sec><jats:title>Background and purpose:<\/jats:title><jats:p>Secretory phospholipase A<jats:sub>2<\/jats:sub> (sPLA<jats:sub>2<\/jats:sub>) is implicated in atherosclerosis, although the effects of specific sPLA<jats:sub>2<\/jats:sub> inhibitors have not been studied. We investigated the effects of the indole analogue indoxam on low\u2010density lipoprotein (LDL) modification by sPLA<jats:sub>2<\/jats:sub> enzymes of different types and on the associated inflammatory responses in human umbilical vein endothelial cells (HUVEC).<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental approach:<\/jats:title><jats:p>LDL modification was assessed by measuring the contents of two major molecular species of lysophosphatidylcholine (LPC) using electrospray ionization\u2010liquid chromatography\/mass spectrometry. The proinflammatory activity of the modified LDL was evaluated by determining monocyte chemoattractant protein\u20101 (MCP\u20101) mRNA expression and transcriptional factor nuclear factor\u2010kappaB (NF\u2010\u03baB) activity in HUVEC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key results:<\/jats:title><jats:p>Indoxam dose\u2010dependently inhibited palmitoyl\u2010 and stearoyl\u2010LPC production in LDL incubated with snake venom sPLA<jats:sub>2<\/jats:sub> (IC<jats:sub>50<\/jats:sub> 1.2\u2003\u03bc<jats:sc>M<\/jats:sc> for palmitoyl\u2010LPC, 0.8\u2003\u03bc<jats:sc>M<\/jats:sc> for stearoyl\u2010LPC). MCP\u20101 mRNA expression and NF\u2010\u03baB activity were enhanced by venom sPLA<jats:sub>2<\/jats:sub>\u2010treated LDL, which was completely suppressed by indoxam but not by thioetheramide\u2010PC, a competitive sPLA<jats:sub>2<\/jats:sub> inhibitor. Indoxam also suppressed LPC production in LDL treated with human synovial type IIA sPLA<jats:sub>2<\/jats:sub>. Tumour necrosis factor \u03b1 (TNF\u03b1) increased type V sPLA2 expression in HUVEC. Indoxam dose\u2010dependently suppressed LPC production in native and glycoxidized LDL treated with TNF\u03b1\u2010stimulated HUVEC. Indoxam suppressed MCP\u20101 mRNA expression and NF\u2010\u03baB activity in TNF\u03b1\u2010stimulated HUVEC incubated with native or glycoxidized LDL.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and implications:<\/jats:title><jats:p>Indoxam prevented sPLA<jats:sub>2<\/jats:sub>\u2010induced LPC production in native and glycoxidized LDL as well as LDL\u2010induced inflammatory activity in HUVEC. Our results suggest that indoxam may be a potentially useful anti\u2010atherogenic agent.<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (2008) <jats:bold>153<\/jats:bold>, 1399\u20131408; doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/bjp.2008.12\">10.1038\/bjp.2008.12<\/jats:ext-link>; published online 11 February 2008<\/jats:p><\/jats:sec>","DOI":"10.1038\/bjp.2008.12","type":"journal-article","created":{"date-parts":[[2008,2,11]],"date-time":"2008-02-11T10:59:26Z","timestamp":1202727566000},"page":"1399-1408","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Secretory PLA<sub>2<\/sub> inhibitor indoxam suppresses LDL modification and associated inflammatory responses in TNF\u03b1\u2010stimulated human endothelial 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