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.