Upregulation of endothelial adhesion molecules by lysophosphatidylcholine. Involvement of G protein-coupled receptor GPR4.
Lysophosphatidylcholine induces expression of adhesion molecules; however, the underlying molecular mechanisms of this are not well elucidated. In this study, the intracellular signaling by which lysophosphatidylcholine upregulates vascular cell adhesion molecule-1 and P-selectin was delineated using YPEN-1 and HEK293T cells. The results showed that lysophosphatidylcholine dose-dependently induced expression of vascular cell adhesion molecule-1 and P-selectin, accompanied by the activation of transcription factor nuclear factor kappaB. However, the nuclear factor kappaB inhibitor caffeic acid phenethyl ester (CAPE) and the antioxidant N-acetylcysteine only partially blocked lysophosphatidylcholine-induced adhesion molecules. Subsequently, we found that the lysophosphatidylcholine receptor G protein-coupled receptor 4 (GPK4) was expressed in YPEN-1 cells and triggered the cAMP/protein kinase A/cAMP response element-binding protein pathway, resulting in upregulation of adhesion molecules. Further evidence showed that overexpression of human GPK4 enhanced lysophosphatidylcholine-induced expression of adhesion molecules in YPEN-1 cells, and enabled HEK293T cells to express adhesion molecules in response to lysophosphatidylcholine. In conclusion, the current study suggested two pathways by which lysophosphatidylcholine regulates the expression of adhesion molecules, the lysophosphatidylcholine/nuclear factor-kappaB/adhesion molecule and lysophosphatidylcholine/GPK4/cAMP/protein kinase A/cAMP response element-binding protein/adhesion molecule pathways, emphasizing the importance of the lysophosphatidylcholine receptor in regulating endothelial cell function.
Zou
Yani
Y
College of Pharmacy, Pusan National University, Gumjung-gu, Busan, Korea.
Kim
Chul H
CH
Chung
Jae H
JH
Kim
Ji Y
JY
Chung
Sang W
SW
Kim
Mi K
MK
Im
Dong S
DS
Lee
Jaewon
J
Yu
Byung P
BP
Chung
Hae Y
HY
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D016328:NF-kappa B / Q000502:physiology; D019007:P-Selectin / Q000096:biosynthesis*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis / Q000502:physiology*; D015398:Signal Transduction; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis*
C091670:GPR4 protein, human; D008244:Lysophosphatidylcholines; D016328:NF-kappa B; D019007:P-Selectin; D043562:Receptors, G-Protein-Coupled; D019010:Vascular Cell Adhesion Molecule-1; D000242:Cyclic AMP; D000111:Acetylcysteine