Gene regulation of heme oxygenase-1 as a therapeutic target.
Heme oxygenase (HO)-1 is the inducible isoform of the rate-limiting enzyme of heme degradation. HO regulates the cellular content of the pro-oxidant heme and produces catabolites with physiological functions. HO-1 is induced by a host of oxidative stress stimuli, and the activation of HO-1 gene expression is considered to be an adaptive cellular response to survive exposure to environmental stresses. Since overexpression of the HO-1 gene is also protective against the deleterious effects of experimental injuries, the specific induction of HO-1 by 'non-stressful' stimuli, eg. stimuli that are not associated with oxidative stress, such as adenosine 3', 5'-cyclic monophosphate or cyclic guanosine 3',5'-monophosphate, may have important clinical implications. This review summarizes recent advances in the understanding of regulatory mechanisms of HO-1 gene expression, in particular the role of various redox-dependent and redox-independent signaling pathways. Models of experimental injuries are highlighted in which specific overexpression of the HO-1 gene either by targeted gene transfer or by pharmacological modulation has been demonstrated to provide therapeutic effects.
Immenschuh
S
S
Zentrum Innere Medizin, Abteilung Gastroenterologie und Endokrinologie, Georg-August-Universität, Göttingen, Germany. simmens@gwdg.de
Ramadori
G
G
D000818:Animals; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D006418:Heme / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics* / Q000627:therapeutic use; D051547:Heme Oxygenase-1; D006801:Humans; D008565:Membrane Proteins; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014947:Wounds and Injuries / Q000517:prevention & control
D008565:Membrane Proteins; D006418:Heme; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1