Impairment of the fibrinolytic system, mostly due to elevated plasma levels of plasminogen activator inhibitor 1 (PAI-1), is often associated with metabolic disorders such as diabetes mellitus and insulin-resistance syndrome. Moreover, insulin, as we have previously shown, directly stimulates PAI-1 production with a mechanism underlying a complex signaling network which ultimately leads to ERK activation. In this study we have analyzed the effects of agonists of the peroxisome proliferator-activated receptor (PPAR) alpha and gamma on PAI-1 biosynthesis in HepG2 cells in the presence or absence of insulin. The high affinity PPARalpha agonist, Wy-14,643, increased basal and insulin-stimulated PAI-1 antigen release with a mechanism involving gene transcription. We then investigated whether the MAP kinase pathway also plays a role in the stimulatory properties of Wy-L4,643. Wy-L4,643 increases phosphorylation of ERK and p38 in a time-dependent manner without affecting that of SAPK/JNK or ERK5. Moreover, the MEK (ERK kinase) inhibitors, PD98059 and UO126, completely prevented PAI-1 induction by Wy-14,643 without inhibiting the activation of a reporter gene carrying the PPRE element. Interestingly, the addition of p38 inhibitor followed by insulin and Wy-14,643 resulted in a greater than additive stimulation of PAI-1 secretion acting through ERK1/2 phosphorylation. In contrast, the synthetic PPARgamma agonist, rosiglitazone, did not change PAI-1 level, although this compound induced transcription from the PPRE-driven luciferase reporter construct. In conclusion, Wy-14,643 induces PAI-1 gene expression, in the presence or absence of insulin, with a mechanism which is independent on PPARalpha activation and requires signaling through the ERK1/2 signaling pathway.
Induction of plasminogen activator inhibitor I by the PPARalpha ligand, Wy-14,643, is dependent on ERK1/2 signaling pathway / C. Banfi, J. Auwerx, F. Poma, E. Tremoli, L. Mussoni. - In: THROMBOSIS AND HAEMOSTASIS. - ISSN 0340-6245. - 90:4(2003 Oct), pp. 611-619.
|Titolo:||Induction of plasminogen activator inhibitor I by the PPARalpha ligand, Wy-14,643, is dependent on ERK1/2 signaling pathway|
BANFI, CRISTINA (Primo)
TREMOLI, ELENA (Penultimo)
MUSSONI, LUCIANA (Ultimo)
|Parole Chiave:||Fibrinolysis; HepG2 cells; MAP kinases; Peroxisome proliferator activated receptor|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||ott-2003|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1267/THRO03040611|
|Appare nelle tipologie:||01 - Articolo su periodico|