Role of lipoprotein-associated lysophospholipids in migratory activity of coronary artery smooth muscle cells.
The migration of vascular smooth muscle cells (SMCs) is a hallmark of the pathogenesis of atherosclerosis and restenosis after angioplasty. Plasma low-density lipoprotein (LDL), but not high-density lipoprotein (HDL), induced the migration of human coronary artery SMCs (CASMCs). Among bioactive lipids postulated to be present in LDL, lysophosphatidic acid (LPA) appreciably mimicked the LDL action. In fact, the LDL-induced migration was markedly inhibited by pertussis toxin, an LPA receptor antagonist Ki-16425, and a small interfering RNA (siRNA) targeted for LPA(1) receptors. Moreover, LDL contains a higher amount of LPA than HDL does. HDL markedly inhibited LPA- and platelet-derived growth factor (PDGF)-induced migration, and sphingosine 1-phosphate (S1P), the content of which is about fourfold higher in HDL than in LDL, mimicked the HDL action. The inhibitory actions of HDL and S1P were suppressed by S1P(2) receptor-specific siRNA. On the other hand, the degradation of the LPA component of LDL by monoglyceride lipase or the antagonism of LPA receptors by Ki-16425 allowed LDL to inhibit the PDGF-induced migration. The inhibitory effect of LDL was again suppressed by S1P(2) receptor-specific siRNA. In conclusion, LPA/LPA(1) receptors and S1P/S1P(2) receptors mediate the stimulatory and inhibitory migration response to LDL and HDL, respectively. The balance of not only the content of LPA and S1P in lipoproteins but also the signaling activity between LPA(1) and S1P(2) receptors in the cells may be critical in determining whether the lipoprotein is a positive or negative regulator of CASMC migration.
Damirin
Alatangaole
A
Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan.
Tomura
Hideaki
H
Komachi
Mayumi
M
Liu
Jin-Peng
JP
Mogi
Chihiro
C
Tobo
Masayuki
M
Wang
Ju-Qiang
JQ
Kimura
Takao
T
Kuwabara
Atsushi
A
Yamazaki
Yuji
Y
Ohta
Hideo
H
Im
Doon-Soon
DS
Sato
Koichi
K
Okajima
Fumikazu
F
D000328:Adult; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000502:physiology*; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology*
D008074:Lipoproteins; D008246:Lysophospholipids