Ether-linked diglycerides inhibit vascular smooth muscle cell growth via decreased MAPK and PI3K/Akt signaling.
Diglycerides (DGs) are phospholipid-derived second messengers that regulate PKC-dependent signaling pathways. Distinct species of DGs are generated from inflammatory cytokines and growth factors. Growth factors increase diacyl- but not ether-linked DG species, whereas inflammatory cytokines predominately generate alkyl, acyl- and alkenyl, acyl-linked DG species in rat mesenchymal cells. These DG species have been shown to differentially regulate protein kinase C (PKC) isotypes. Ester-linked diacylglycerols activate PKC-epsilon and cellular proliferation in contrast to ether-linked DGs, which lead to growth arrest through the inactivation of PKC-epsilon. It is now hypothesized that ether-linked DGs inhibit mitogenesis through the inactivation of ERK and/or Akt signaling cascades. We demonstrate that cell-permeable ether-linked DGs reduce vascular smooth muscle cell growth by inhibiting platelet-derived growth factor-stimulated ERK in a PKC-epsilon-dependent manner. This inhibition is specific to the ERK pathway, since ether-linked DGs do not affect growth factor-induced activation of other family members of the MAPKs, including p38 MAPK and c-Jun NH(2)-terminal kinases. We also demonstrate that ether-linked DGs reduce prosurvival phosphatidylinositol 3-kinase (PI3K)/Akt signaling, independent of PKC-epsilon, by diminishing an interaction between the subunits of PI3K and not by affecting protein phosphatase 2A or lipid (phosphatase and tensin homologue deleted in chromosome 10) phosphatases. Taken together, our studies identify ether-linked DGs as potential adjuvant therapies to limit vascular smooth muscle migration and mitogenesis in atherosclerotic and restenotic models.
Houck
Kristy L
KL
Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania 17033, USA.
Fox
Todd E
TE
Sandirasegarane
Lakshman
L
Kester
Mark
M
D000818:Animals; D000077214:Becaplermin; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004075:Diglycerides / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005995:Glyceryl Ethers / Q000378:metabolism*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D032389:Myocytes, Smooth Muscle / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
C520323:1-oleoyl-2-acetoyl-sn-glycerol; D004075:Diglycerides; D005995:Glyceryl Ethers; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; C055394:1-palmityl-2-acetylglycerol; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051744:Protein Kinase C-epsilon; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3