Atherogenic role of lysophosphatidylcholine in low-density lipoprotein modified by phospholipase A2 and in diabetic patients: protection by nitric oxide donor.
The aim of our study was to investigate the atherogenic role of lysophosphatidylcholine (lyso-PC) in low-density lipoprotein (LDL) under diabetic environment. Expression of monocyte chemoattractant protein-1 (MCP-1) mRNA and nuclear factor-kappa B (NF-kappaB)-DNA binding activity were determined in human umbilical vein endothelial cells (HUVEC) incubated with native or glycoxidized LDL, LDL modified by phospholipase A2 (PLA2) and LDL isolated from diabetic patients. Lyso-PC contents in LDL were measured using electrospray ionization-liquid chromatography/mass spectrometry (ESI-LC/MS). Lyso-PC contents were higher in glycoxidized LDL and PLA2-treated LDL compared with native LDL. Glycoxidized LDL and enrichment of lyso-PC by PLA2 treatment resulted in upregulation of MCP-1 mRNA expression through increased NF-kappaB activity in HUVEC. Moreover, LDL isolated from diabetics contained more lyso-PC than that from nondiabetic subjects, and induced higher MCP-1 mRNA expression and NF-kappaB activity in HUVEC. In both in vitro and human studies, palmitoyl- and stearoyl-lyso-PC contents correlated with MCP-1 expression and NF-kappaB activity. Preincubation with 4-ethyl-2-hydroxyimino-5-nitro-3-hexenamide, a NO donor, abrogated increased expression of MCP-1 mRNA and high NF-kappaB activity induced by PLA2-treated LDL and by LDL isolated from diabetic patients. Our results suggest that lyso-PC contents in LDL play an important role in atherogenesis under diabetic condition, which could be prevented by increased availability of vascular NO.
Sonoki
Kazuo
K
Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Iwase
Masanori
M
Iino
Kenzo
K
Ichikawa
Kojiro
K
Ohdo
Shigehiro
S
Higuchi
Shun
S
Yoshinari
Mototaka
M
Iida
Mitsuo
M
D001161:Arteriosclerosis / Q000097:blood / Q000209:etiology*; D018932:Chemokine CCL2 / Q000235:genetics; D004247:DNA / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D004730:Endothelium, Vascular / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008077:Lipoproteins, LDL / Q000097:blood* / Q000737:chemistry / Q000494:pharmacology; D008244:Lysophosphatidylcholines / Q000032:analysis* / Q000097:blood; D016328:NF-kappa B / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009574:Nitro Compounds / Q000494:pharmacology; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D012333:RNA, Messenger / Q000032:analysis; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D014471:Umbilical Veins
D018932:Chemokine CCL2; D008077:Lipoproteins, LDL; D008244:Lysophosphatidylcholines; D016328:NF-kappa B; D020030:Nitric Oxide Donors; D009574:Nitro Compounds; D012333:RNA, Messenger; D017392:Thiobarbituric Acid Reactive Substances; C099252:oxidized low density lipoprotein; C006065:We 201; C026564:stearoyl alpha-lysolecithin; D004247:DNA; C061872:FK 409; D010741:Phospholipases A; D054467:Phospholipases A2