Reduced nitric oxide production by endothelial cells in cirrhotic rat liver: Endothelial dysfunction in portal hypertension

Altered Endothelin-1 Signaling in Production of Thromboxane A2 in Kupffer Cells from Bile Duct Ligated Rats

“…The overproduction of vasoconstrictive endothelin-1 (ET-1) is a hallmark of the portal hypertension associated with disruption of the hepatic microcirculation during the development of fibrosis and cirrhosis (1)(2)(3)(4). Thromboxane A 2 (TXA 2 ) is a potent cyclooxygenase (COX)-derived vasoconstrictor in the portal circulation and contributes to the overall vascular tone of the hepatic microcirculation (5)(6)(7).…”

“…The translocation of cPLA 2 from the cytosol to its target membrane is dependent on intracellular [Ca2+], which binds to the N-terminal C2 domain. This domain is a Ca 2+ and phospholipid binding domain that promotes interaction of cPLA 2 with its target membrane. Although the phosphorylation of Ser505 by p38 mitogen activated protein kinase (p38 MAPK) and extracellular signal-regulated kinase 1/2 (ERK1/2) (29-31), Ser515 by Ca 2+ /Calmodulin protein kinase II (CaMKII) (32), and Ser727 by MAPK interacting kinase I (Mnk1) (33) have been implicated in the activation of cPLA 2 ; several studies have established that the phosphorylation of Ser505 is critical for maximal activation of cPLA 2 in most cell types in response to agonist stimulation in vivo and in vitro (26,(29)(30)(31)(34)(35)(36)(37).…”

“…Several studies have reported that ET-1 induces the activation of cPLA 2 with the subsequent release of various AA-derived eicosanoids, including TXA 2 , in many cell types by binding to Gq/G11 and Gi coupled ET (A) and ET (B) receptors. The stimulation of Gq has been shown to induce the activation of cPLA 2 and production of eicosanoids via the PLC or PKC mediated activation of ERK1/2.…”

“…The stimulation of Gq has been shown to induce the activation of cPLA 2 and production of eicosanoids via the PLC or PKC mediated activation of ERK1/2. Stimulation of Gi coupled receptors have been reported to lead to the phosphorylation of cPLA 2 and release of AA via the activation of p38 MAPK and ERK1/2, although the intermediates involved in the activation of p38 have not been fully elucidated (38)(39)(40)(41)(42)(43)(44)(45)(46)(47).…”

“…Production of TXA 2 is controlled by cytosolic phospholipase A 2 (cPLA 2 ) that is activated by the interaction of entothelin-1 (ET-1) with its G-protein coupled ET receptor B (ETBR). However, the signaling pathways that contribute to the ET-1-induced activation of cPLA 2 …”