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Transcriptional Activation Of The Haem Oxygenase-1 Gene By CGMP Via A CAMP Response Element/activator Protein-1 Element In Primary Cultures Of Rat Hepatocytes

Stephan IMMENSCHUH, Vera HINKE, Andreas OHLMANN, Susanne GIFHORN-KATZ, Norbert KATZ, Kurt JUNGERMANN, Thomas KIETZMANN

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The expression of the rate-limiting enzyme of haem degradation, haem oxygenase-1 (HO-1), can be induced by various stimuli, including lipopolysaccharide, tumour necrosis factor α and NO. The NO signal can be transmitted by cGMP, therefore this study was aimed at testing the activation of the HO-1 gene by cGMP. In primary cultures of rat hepatocytes, both HO-1 mRNA and protein were induced by the NO donor sodium nitroprusside and 8-bromo-cGMP. The HO-1 mRNA induction by cGMP was prevented by the specific protein kinase G inhibitor KT5823. The cGMP-dependent HO-1 mRNA induction was dose-dependent and transcriptionally regulated, as determined by studies with actinomycin D and a nuclear run-on assay. Cycloheximide lowered the cGMP-dependent induction of HO-1 mRNA to about one half. Luciferase reporter constructs driven by about 800 bp of the 5´-flanking region of the rat HO-1 gene were transiently transfected into primary rat hepatocytes; 8-bromo-cGMP caused a 6-fold induction, which was obliterated by deletion and mutation of the cAMP response element/activator protein-1 (CRE/AP-1) (-665/-654) site. Thus HO-1 induction by cGMP appears to be stimulated by the protein kinase G pathway and may be mediated mainly via a CRE/AP-1 element in the rat HO-1 promoter.