PMID- 18264128
OWN - NLM
STAT- MEDLINE
DCOM- 20080623
LR  - 20211020
IS  - 0007-1188 (Print)
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Linking)
VI  - 153
IP  - 7
DP  - 2008 Apr
TI  - Secretory PLA2 inhibitor indoxam suppresses LDL modification and associated 
      inflammatory responses in TNFalpha-stimulated human endothelial cells.
PG  - 1399-408
LID - 10.1038/bjp.2008.12 [doi]
AB  - BACKGROUND AND PURPOSE: Secretory phospholipase A2 (sPLA2) is implicated in 
      atherosclerosis, although the effects of specific sPLA2 inhibitors have not been 
      studied. We investigated the effects of the indole analogue indoxam on 
      low-density lipoprotein (LDL) modification by sPLA2 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-kappaB) activity in HUVEC. KEY RESULTS: Indoxam 
      dose-dependently inhibited palmitoyl- and stearoyl-LPC production in LDL 
      incubated with snake venom sPLA2 (IC50 1.2 microM for palmitoyl-LPC, 0.8 microM 
      for stearoyl-LPC). MCP-1 mRNA expression and NF-kappaB activity were enhanced by 
      venom sPLA2-treated LDL, which was completely suppressed by indoxam but not by 
      thioetheramide-PC, a competitive sPLA2 inhibitor. Indoxam also suppressed LPC 
      production in LDL treated with human synovial type IIA sPLA2. Tumour necrosis 
      factor alpha (TNFalpha) increased type V sPLA2 expression in HUVEC. Indoxam 
      dose-dependently suppressed LPC production in native and glycoxidized LDL treated 
      with TNFalpha-stimulated HUVEC. Indoxam suppressed MCP-1 mRNA expression and 
      NF-kappaB activity in TNFalpha-stimulated HUVEC incubated with native or 
      glycoxidized LDL. CONCLUSIONS AND IMPLICATIONS: Indoxam prevented sPLA2-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.
FAU - Sonoki, K
AU  - Sonoki K
AD  - Department of Medicine and Clinical Science, Graduate School of Medical Sciences, 
      Kyushu University, Fukuoka, Japan.
FAU - Iwase, M
AU  - Iwase M
FAU - Sasaki, N
AU  - Sasaki N
FAU - Ohdo, S
AU  - Ohdo S
FAU - Higuchi, S
AU  - Higuchi S
FAU - Takata, Y
AU  - Takata Y
FAU - Iida, M
AU  - Iida M
LA  - eng
PT  - Journal Article
DEP - 20080211
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Carbamates)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Indolizines)
RN  - 0 (Lipoproteins, LDL)
RN  - 0 (Lysophosphatidylcholines)
RN  - 0 (NF-kappa B)
RN  - 0 (Phospholipase A2 Inhibitors)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (indoxam)
SB  - IM
MH  - Carbamates/administration & dosage/*pharmacology
MH  - Cells, Cultured
MH  - Chemokine CCL2/drug effects/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Endothelium, Vascular/drug effects/metabolism
MH  - Enzyme Inhibitors/administration & dosage/*pharmacology
MH  - Gene Expression Regulation/drug effects
MH  - Humans
MH  - Indolizines/administration & dosage/*pharmacology
MH  - Lipoproteins, LDL/drug effects/metabolism
MH  - Lysophosphatidylcholines/metabolism
MH  - NF-kappa B/drug effects/metabolism
MH  - *Phospholipase A2 Inhibitors
MH  - RNA, Messenger/drug effects/metabolism
MH  - Tumor Necrosis Factor-alpha/*drug effects/metabolism
MH  - Umbilical Veins/cytology/metabolism
PMC - PMC2437901
EDAT- 2008/02/12 09:00
MHDA- 2008/06/24 09:00
PMCR- 2009/04/01
CRDT- 2008/02/12 09:00
PHST- 2008/02/12 09:00 [pubmed]
PHST- 2008/06/24 09:00 [medline]
PHST- 2008/02/12 09:00 [entrez]
PHST- 2009/04/01 00:00 [pmc-release]
AID - bjp200812 [pii]
AID - 10.1038/bjp.2008.12 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2008 Apr;153(7):1399-408. doi: 10.1038/bjp.2008.12. Epub 2008 Feb 
      11.