TY - JOUR
T1 - Very low density lipoprotein-mediated signal transduction and plasminogen activator inhibitor type 1 in cultured HepG2 cells
AU - Banfi, Cristina
AU - Mussoni, Luciana
AU - Risé, Patrizia
AU - Cattaneo, Maria Grazia
AU - Vicentini, Lucia
AU - Battaini, Fiorenzo
AU - Galli, Claudio
AU - Tremoli, Elena
PY - 1999/7/23
Y1 - 1999/7/23
N2 - 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- [3H]inositol-labeled HepG2 cells, VLDL (100 μg/mL) caused a time-dependent increase in [3H]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 P2+ release from intracellular stores, inhibited VLDL-induced PAI-1 secretion by 60% (P
AB - 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- [3H]inositol-labeled HepG2 cells, VLDL (100 μg/mL) caused a time-dependent increase in [3H]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 P2+ release from intracellular stores, inhibited VLDL-induced PAI-1 secretion by 60% (P
KW - Fibrinolysis
KW - Hepatoma cell line
KW - Plasminogen activator inhibitor type 1
KW - Signaling
KW - VLDL
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UR - http://www.scopus.com/inward/citedby.url?scp=0033597961&partnerID=8YFLogxK
M3 - Article
C2 - 10417403
AN - SCOPUS:0033597961
VL - 85
SP - 208
EP - 217
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 2
ER -