Reference:
Marathe, G.K., S.S. Davies, K.A. Harrison, A.R. Silva, R.C. Murphy,
H. Castro-Faria-Neto, S.M. Prescott, G.A. Zimmerman, and T.M. McIntyre.
(1999). Inflammatory platelet-activating factor-like phospholipids
in oxidized low density lipoproteins are fragmented alkyl phosphatidylcholines. J Biol Chem 274:28395-40.
Abstract: Oxidation of human low density lipoprotein (LDL) generates
proinflammatory mediators and underlies early events in atherogenesis.
We identified mediators in oxidized LDL that induced an inflammatory
reaction in vivo, and activated polymorphonuclear leukocytes and
cells ectopically expressing human platelet-activating factor (PAF)
receptors. Oxidation of a synthetic phosphatidylcholine showed that
an sn-1 ether bond confers an 800-fold increase in potency. This
suggests that rare ether-linked phospholipids in LDL are the likely
source of PAF-like activity in oxidized LDL. Accordingly, treatment
of oxidized LDL with phospholipase A(1) greatly reduced phospholipid
mass, but did not decrease its PAF-like activity. Tandem mass spectrometry
identified traces of PAF, and more abundant levels of 1-O-hexadecyl-2-(butanoyl
or butenoyl)-sn-glycero-3-phosphocholines (C(4)-PAF analogs) in
oxidized LDL that comigrated with PAF-like activity. Synthesis showed
that either C(4)-PAF was just 10-fold less potent than PAF as a
PAF receptor ligand and agonist. Quantitation by gas chromatography-mass
spectrometry of pentafluorobenzoyl derivatives shows the C(4)-PAF
analogs were 100-fold more abundant in oxidized LDL than PAF. Oxidation
of synthetic alkyl arachidonoyl phosphatidylcholine generated these
C(4)-PAFs in abundance. These results show that quite minor constituents
of the LDL phosphatidylcholine pool are the exclusive precursors
for PAF-like bioactivity in oxidized LDL. |
