Relationship of molecular structure to the mechanism of lysophospholipid-induced smooth muscle cell proliferation

Abstract

We previously reported that oxidized low-density lipoprotein and one of its constituents, lysophosphatidylcholine (lysoPC), caused smooth muscle cell proliferation that was inhibitable by vitamin E and by a neutralizing antibody against basic fibroblast growth factor-2 (FGF-2). We now show that the mitogenic activity of lysolipids is highly dependent on structure. Phospholipids with palmitoyl fatty acid and phosphocholine induced DNA synthesis optimally. Shorter and longer fatty acids were significantly less potent, as were phosphoserine and phosphoethanolamine head groups. Structurally related phospholipids [platelet-activating factor (PAF) and lysoPAF] were also mitogens and acted via an analogous FGF-2-dependent, vitamin E-inhibitable mechanism. The mechanism of lysoPC stimulation was distinct from that of another phospholipid mitogen, lysophosphatidic acid (lysoPA), in that lysoPC stimulation was not pertussis toxin inhibitable. Furthermore, lysoPA stimulation was not inhibitable by vitamin E. Despite its distinct cellular pathway for stimulation, lysoPA also ultimately led to FGF-2 release. Our data show that specific structural attributes of lysoPC, PAF, and lysoPAF enable these agents to mediate smooth muscle cell release of FGF-2, which in turn stimulates proliferation.

RanGAP-Mediated Nuclear Protein Import in Vascular Smooth Muscle Cells Is Augmented by Lysophosphatidylcholine

“…We speculate that the difference in monoacyl LPC and LPLC on nuclear protein import was probably due to the disparate molecular impact of the ester-linked and vinyl ether-linked aliphatic groups on the putative phosphocholine binding pocket. These data are consistent with recent findings that the phosphocholine head group was necessary for the stimulation of DNA synthesis in smooth muscle cells (Chai et al, 2000).…”

Platelet‐activating factor and liver metastasis of colorectal cancer

“…During the past decade, in vitro data and animal studies have highlighted that PAF is a proangiogenic molecule that mediates vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) effects. [23][24][25][26][27] We thus investigated if tissue PAF values might be correlated with those of VEGF and bFGF; these angiogenic growth factors being detected by specific ELISA assays (DuoSet, R&D Systems Europe, Oxon, U.K.) as previously described. 28 Regression analysis highlighted a significant link between PAF values and those of VEGF (r ϭ 0.34; p ϭ 0.009) and bFGF (r ϭ 0.49; p ϭ 0.0001).…”

Pancreatic Bile Salt-Dependent Lipase Induces Smooth Muscle Cells Proliferation

“…4 LysoPC attracted monocytes/macrophages further, leading to foam cells 7 and altered various intracellular signaling pathways. 8 As a consequence, lysoPC has growth-promoting effects on smooth muscle cells (SMCs) that play a central feature in the development of atherosclerotic lesions. Therefore, endothelial BSDL may hydrolyze lysoPC to decrease the attraction of monocytes and the formation of foam cells or could lower SMC proliferation by decreasing the level of lipid second messenger (lysoPC 8 or ceramide 9 -11 ) in the intima.…”

“…8 As a consequence, lysoPC has growth-promoting effects on smooth muscle cells (SMCs) that play a central feature in the development of atherosclerotic lesions. Therefore, endothelial BSDL may hydrolyze lysoPC to decrease the attraction of monocytes and the formation of foam cells or could lower SMC proliferation by decreasing the level of lipid second messenger (lysoPC 8 or ceramide 9 -11 ) in the intima. However, BSDL could evoke SMC proliferation by generating lysoPC or free oleic acid 12 from phosphatidylcholine (PC).…”