4-Hydroxynonenal signalling to apoptosis in isolated rat hepatocytes: The role of PKC-δ

PKC signaling in oxidative hepatic damage

“…Moreover, we have found that pathophysiological concentrations of HNE (0.1 lM) are responsible for PKC-b activation in rat hepatocytes and for the up regulation of transport, maturation and secretion of cathepsin D (Chiarpotto et al, 1999); in HNE-treated J774 macrophages PKC-b activation up regulates monocyte chemoattractant protein (MCP-1) (Nitti et al, 2002) thereby sustaining a general mechanism by which low doses of HNE activate PKC-b isoenzymes and stimulate protein secretion (Marinari et al, 2003). Higher doses of HNE are also able to activate PKC-d isoform, leading to hepatocyte apoptosis (Castello et al, 2005). More recently, it has been reported that ethanol-induced oxidative stress and PKC activation play also a central role in the up regulation of collagen I, a key feature of liver fibrosis (Nieto, 2007).…”

Signaling and cytotoxic functions of 4-hydroxyalkenals

“…Many excellent reviews have been published over the years, summarizing both signaling and cytotoxic effects of this molecule (19,28,29,32,38,70,74,76,101,110). Among the various signaling targets of 4-HNE, the following are particularly interesting: c-Jun NH 2 -terminal kinase (JNK) (11), p38 mitogen-activated protein kinases (p38 MAPK) (111), cell cycle regulators (8), and protein kinase-␤ and -␦ (PKC␤ and PKC␦) (16,23). However, the underlying notion that 4-HNE acts like a classical ligand that interacts with binding/catalytic sites in proteins is in most cases unfounded.…”

Role of 4-hydroxynonenal and its metabolites in signaling

“…6 These studies are consistent with results of investigations showing that when K562, HLE B-3, or HL-60 cells are transfected with glutathione transferaseA4-4 (GSTA4-4), the growth rate of these cells increases with a concomitant decrease in HNE levels. [7][8][9] Empty vectortransfected cells used as controls have no effect on HNE levels or the rate of cell growth, suggesting that increased 27 Mitogenic response Rat epithelial type II cells 28 Induction of γ-GGT via EpRE/Nrf2 Vascular cells and atherosclerotic lesions 29 Desensitization of platelet derived growth factor receptor β Caco-2 human adenocarcinoma cells 30 Antiproliferative effects Rat hepatocytes 31 Apoptotic signaling through PKC δ Alteration in gene expression PC12 cells 32 Adaptive response and enhancement of cell tolerance through induction of thioredoxin reductase via activation of Nrf-2 HLE B-3 cells 12 Profound changes in gene expression upon depletion of 4-HNE Pulmonary epithelial cells 33 Increases heme oxygenase-1 through activation of the ERK pathway Human fetal liver hematopoietic stem cells 34 Inhibits cell proliferation and alters differentiation pathways Human cell lines of varying origin 35 Modulation of signaling kinases Human neuroblastoma cells 36 Regulation of glycogen synthase kinase 3β Human lens epithelial cells 9 HNE depletion leads to phenotypic transformation of adherent cells HL60 and HLE B-3 cells 3,8 Induction of apoptosis Human hepatic stellate cells 37,38 Pro-fibrogenic stimulus Interaction with JNK isoforms Human erythroleukemic cells 19 Regulation of UVA-mediated signaling for apoptosis Cells of varying origin 25 Triggers multistep signal transduction for suppression of cellular functions K562, HL60, HLE B-3 (see review by Awasthi et al 3 ) Role in stress-mediated signaling Jurkat cells 39 Down-regulation of Akt kinase Macrophages 40 Activation of PKC β isoforms K562 cells 18 Role in adaptive response of cells to heat and oxidative stress Hepatic stellate cells 41 Reduces tyrosine phosphorylation Human epidermoid carcinoma A431 cells 42 Triggers an epide...…”