Induction of heme oxygenase-1 and heat shock protein 70 in rat hepatocytes: the role of calcium signaling.
Stress response genes including heat shock proteins are induced under a variety of conditions to confer cellular protection. This study investigated the role of calcium signaling in the induction of two stress response genes, heme oxygenase-1/hsp32 and hsp70, in isolated rat hepatocytes. Both genes were induced by cellular glutathione depletion. This induction could be inhibited by BAPTA-AM. Culturing in a calcium-free medium prevented the induction of hsp70 gene expression after glutathione depletion without affecting heme oxygenase-1 gene expression. Thapsigargin increased the gene expression of heme oxygenase-1 but not that of hsp70. Thapsigargin-induced heme oxygenase-1 induction was completely inhibited by BAPTA-AM. Incubation with the Ca(2+)-ionophore A23187 augmented heme oxygenase-1 (two-fold) and hsp70 (5.2-fold) mRNA levels. Our data suggests a significant role of Ca(2+)-dependent pathways in the induction of the two stress genes. An increase in the cytoplasmic Ca(2+) activity seems to play a key role in the cascade of signaling leading to the induction of the two genes. However, the source of Ca(2+) that fluxes into the cytoplasm seems to be different. Our data provides evidence for a compartmentalization of calcium fluxes, i.e. the Ca(2+) flux from intracellular stores (e.g. the endoplasmic reticulum) plays a major role in the induction of heme oxygenase-1. By contrast, Ca(2+) flux from the extracellular medium seems to be a mechanism initiating the cellular signaling cascade leading to hsp70 gene induction.
Silomon
Malte
M
Department of Anesthesiology and Critical Care Medicine, University of Saarland, Homburg, Saar, Germany.
Bauer
Inge
I
Bauer
Michael
M
Nolting
Julia
J
Paxian
Markus
M
Rensing
Hauke
H
D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D006706:Homeostasis / Q000187:drug effects; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019284:Thapsigargin / Q000494:pharmacology; D015533:Transcriptional Activation
D002614:Chelating Agents; D018840:HSP70 Heat-Shock Proteins; D012333:RNA, Messenger; D000001:Calcimycin; D019284:Thapsigargin; D051547:Heme Oxygenase-1; D005978:Glutathione; D002118:Calcium