Premium
Altered Endothelin‐1 Signaling in the Activation of Cytosolic Phospholipase A 2 (cPLA 2 ) and Thromboxane A 2 (TXA 2 ) Productions in Kupffer Cells (KC) of the Prefibrotic Rat Liver: A Possible Mechanism in the Early Development of Portal Hypertension in Cirrhosis
Author(s) -
Miller Andrew M,
Zhang Jian X.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1190.14
Subject(s) - phosphorylation , phospholipase c , signal transduction , thromboxane , pertussis toxin , chemistry , medicine , mapk/erk pathway , endocrinology , bapta , p38 mitogen activated protein kinases , platelet , receptor , g protein , biochemistry
We sought to investigate altered ET‐1 signaling in cPLA 2 activation in liver fibrosis. KC isolated from rats of 1 week bile duct ligation (BDL) or sham operation were treated with ET‐1 following pretreatment with inhibitors of Gi or Gq/G11 and intermediates in the signaling pathways. The activation of cPLA 2 measured by phosphorylation and TXA 2 productions in KC were determined. Inhibitions of cPLA 2 with AACOCF3 or [Ca 2+ ] i chelation with BAPTA‐AM, respectively, completely abolished ET‐1 induced releases of TXA 2 from KC of both Sham and BDL, indicating that KC productions of TXA 2 in response to ET‐1 are mediated primarily by Ca 2+ dependent cPLA 2 . Inhibitions of MEK1/2‐ERK1/2 pathway with PD98059 or Gq signaling with GP2A, respectively, completely in Sham but only partially in BDL abrogated releases of TXA 2 in ET‐1 stimulated KC. The inhibition of p38 MAPK with SB203580 or the blockade of Gi using pertussis toxin had no effect in Sham while markedly abolished ET‐1 induced releases of TXA 2 in BDL. In addition, BDL resulted in a significant increase in Gαi but decrease in Gqα and G11α compared to Sham. While BDL caused no significant change in the phosphorylation of ERK1/2 in KC in response to ET‐1, it greatly enhanced the phosphorylation of p38 MAPK compared to Sham. All data suggest that ET‐1 signaling in cPLA 2 activation may shift from Gq/G11 mediated activations of MEK12‐ERK1/2 to Gi mediated activations of p38 MAPK in KC in response to fibrosis.