In normal subjects and in patients with cardiovascular disease, plasma triglycerides are positively correlated with plasminogen activator inhibitor type 1 (PAI-1) levels. Moreover, in vitro studies indicate that VLDLs induce PAI-1 synthesis in cultured cells, ie, endothelial and HepG2 cells. However, the signaling pathways involved in the effect of VLDL on PAI-1 synthesis have not yet been investigated. We report that VLDLs induce a signaling cascade that leads to an enhanced secretion of PAI-1 by HepG2 cells. In myo-[(3)H]inositol-labeled HepG2 cells, VLDL (100 microg/mL) caused a time-dependent increase in [(3)H]inositol phosphates, the temporal sequence being tris>bis>monophosphate. VLDL brought about a time-dependent stimulation of membrane-associated protein kinase C (PKC) activity and arachidonate release. Finally, VLDL stimulated mitogen-activated protein (MAP) kinase, and this effect was reduced by 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7), which suggests that PKC plays a pivotal role in MAP kinase phosphorylation. VLDL-induced PAI-1 secretion was completely prevented by U73122, a specific inhibitor of phosphatidylinositol-specific phospholipase C, by H7 or by PKC downregulation, and by mepacrine (all P<0.01 versus VLDL-treated cells). 3,4,5-Trimethoxybenzoic acid 8-(diethylamino)-octyl ester, which prevents Ca2+ release from intracellular stores, inhibited VLDL-induced PAI-1 secretion by 60% (P<0.05), and the MAP kinase/extracellular signal-regulated kinase kinase (MEK) inhibitor PD98059 completely suppressed both basal and VLDL-induced PAI-1 secretion. These data demonstrate that VLDL-induced PAI-1 biosynthesis results from a principal signaling pathway involving PKC-mediated MAP kinase activation.
Banfi, C., Mussoni, L., Risé, P., Cattaneo, M.G., Vicentini, L., Battaini, F., et al. (1999). Very low density lipoprotein-mediated signal transduction and plasminogen activator inhibitor type 1 in cultured HepG2 cells. CIRCULATION RESEARCH, 85(2), 208-217.
|Tipologia:||Articolo su rivista|
|Citazione:||Banfi, C., Mussoni, L., Risé, P., Cattaneo, M.G., Vicentini, L., Battaini, F., et al. (1999). Very low density lipoprotein-mediated signal transduction and plasminogen activator inhibitor type 1 in cultured HepG2 cells. CIRCULATION RESEARCH, 85(2), 208-217.|
|IF:||Con Impact Factor ISI|
|Settore Scientifico Disciplinare:||Settore BIO/14|
|Revisione (peer review):||Sì, ma tipo non specificato|
|Stato di pubblicazione:||Pubblicato|
|Data di pubblicazione:||1999|
|Titolo:||Very low density lipoprotein-mediated signal transduction and plasminogen activator inhibitor type 1 in cultured HepG2 cells|
|Autori:||Banfi, C; Mussoni, L; Risé, P; Cattaneo, MG; Vicentini, L; Battaini, F; Galli, C; Tremoli, E|
|Appare nelle tipologie:||01 - Articolo su rivista|