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(Circulation Research. 1995;77:530-535.)
© 1995 American Heart Association, Inc.

Articles

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

Hiroshi Ochi, Noriaki Kume, Eiichiro Nishi, Toru Kita

From the Department of Geriatric Medicine, Faculty of Medicine, Kyoto University, Japan.

Correspondence to Noriaki Kume, MD, PhD, Department of Geriatric Medicine, Faculty of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606, Japan.

Abstract 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.

Key Words: protein kinase C • platelet-derived growth factor–B chain • intercellular adhesion molecule-1 • cAMP • lysophosphatidylcholine

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