Elevated levels of cAMP inhibit protein kinase C--independent mechanisms of endothelial platelet-derived growth factor-B chain and intercellular adhesion molecule-1 gene induction by lysophosphatidylcholine.
Lysophosphatidylcholine (lyso-PC), a polar phospholipid product increased in atherogenic lipoproteins and atherosclerotic lesions, has been shown to differentially induce functional intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 and mRNA for platelet-derived growth factor (PDGF)-A and -B chains and heparin-binding epidermal growth factor-like growth factor in various cultured endothelial cells. In this study, we have demonstrated increased expression of cell- and matrix-associated forms of PDGF-B chain (PDGF-B) protein elicited by lyso-PC and further characterized potential signal transduction mechanisms responsible for lyso-PC-induced gene expression, focusing on PDGF-B and ICAM-1 genes in cultured human umbilical vein endothelial cell models. Cycloheximide almost completely inhibited PDGF-B but not ICAM-1 mRNA induction elicited by lyso-PC, suggesting that dependence on de novo protein synthesis for PDGF-B is different from that for ICAM-1. Prolonged exposure to phorbol myristate acetate (PMA), which depletes protein kinase C (PKC), or staurosporine, a PKC inhibitor, did not block lyso-PC-induced increases in PDGF-B or ICAM-1 mRNA. Forskolin and dibutyryl cAMP, which elevate intracellular cAMP levels, blocked both PDGF-B and ICAM-1 upregulation elicited by lyso-PC; however, these cAMP-elevating agents did not suppress ICAM-1 upregulation by PMA. Taken together, PDGF-B and ICAM-1 gene induction by lyso-PC may involve different signaling mechanisms; however, both appear to be independent of PMA-regulatable PKC activation but are suppressed by increased levels of intracellular cAMP.
Ochi
H
H
Department of Geriatric Medicine, Faculty of Medicine, Kyoto University, Japan.
Kume
N
N
Nishi
E
E
Kita
T
T
D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics*; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis / Q000235:genetics*; D011493:Protein Kinase C / Q000502:physiology*; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015533:Transcriptional Activation
D008244:Lysophosphatidylcholines; D010982:Platelet-Derived Growth Factor; D018799:Intercellular Adhesion Molecule-1; D000242:Cyclic AMP; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate