Secretory PLA 2 inhibitor indoxam suppresses LDL modification and associated inflammatory responses in TNFα-stimulated human endothelial cells

K. Sonoki, M. Iwase, N. Sasaki, S. Ohdo, S. Higuchi, Y. Takata, M. Iida

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13 Citations (Scopus)

Abstract

Background and purpose: Secretory phospholipase A 2 (sPLA 2) is implicated in atherosclerosis, although the effects of specific sPLA 2 inhibitors have not been studied. We investigated the effects of the indole analogue indoxam on low-density lipoprotein (LDL) modification by sPLA 2 enzymes of different types and on the associated inflammatory responses in human umbilical vein endothelial cells (HUVEC). Experimental approach: LDL modification was assessed by measuring the contents of two major molecular species of lysophosphatidylcholine (LPC) using electrospray ionization-liquid chromatography/mass spectrometry. The proinflammatory activity of the modified LDL was evaluated by determining monocyte chemoattractant protein-1 (MCP-1) mRNA expression and transcriptional factor nuclear factor-kappaB (NF-κB) activity in HUVEC. Key results: Indoxam dose-dependently inhibited palmitoyl- and stearoyl-LPC production in LDL incubated with snake venom sPLA 2 (IC 50 1.2 μM for palmitoyl-LPC, 0.8 μM for stearoyl-LPC). MCP-1 mRNA expression and NF-κB activity were enhanced by venom sPLA 2-treated LDL, which was completely suppressed by indoxam but not by thioetheramide-PC, a competitive sPLA 2 inhibitor. Indoxam also suppressed LPC production in LDL treated with human synovial type IIA sPLA 2. Tumour necrosis factor α (TNFα) increased type V sPLA2 expression in HUVEC. Indoxam dose-dependently suppressed LPC production in native and glycoxidized LDL treated with TNFα-stimulated HUVEC. Indoxam suppressed MCP-1 mRNA expression and NF-κB activity in TNFα-stimulated HUVEC incubated with native or glycoxidized LDL. Conclusions and implications: Indoxam prevented sPLA 2-induced LPC production in native and glycoxidized LDL as well as LDL-induced inflammatory activity in HUVEC. Our results suggest that indoxam may be a potentially useful anti-atherogenic agent.

Original languageEnglish
Pages (from-to)1399-1408
Number of pages10
JournalBritish Journal of Pharmacology
Volume153
Issue number7
DOIs
Publication statusPublished - Apr 1 2008

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All Science Journal Classification (ASJC) codes

  • Pharmacology

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