Preface [Hot topic: Modulation of Heme Oxygenase-1 as a Therapeutic Target (Executive Editor : M.J. Alcaraz)]

Heme oxygenase (HO) is the enzyme catalyzing the degradation of the heme group that produces carbon monoxide (CO), biliverdin and iron. Biliverdin is converted to bilirubin by biliverdin reductase, and iron is used in metabolism or sequestered by ferritin. HO-2 and HO-3 are constitutive isozymes, whereas HO-1 is induced by a variety of stimuli, many of them related to oxidative stress. This inducible isozyme is also a heat shock protein (HSP32). Despite the fact that bilirubin and CO are toxic at high concentrations and that free iron catalyzes the formation of free radicals and induces oxidative stresss, many lines of evidence indicate that HO-1 induction plays a protective role and can be considered part of a defensive response against stress. Expression of HO-1 has been reported in association with a wide range of conditions including fever and inflammation, ischemia / reperfusion damage, endotoxic shock, atherosclerosis, etc. In particular, Dr. Perrella and Dr. Yet [1] have presented data supporting the hypothesis that HO-1 plays an important role in regulating cardiovascular function, with protective effects on ischemia / reperfusion injury. Recent evidence also indicates the participation of HO in pathological situations such as atherosclerosis and restenosis. The mechanisms involved in vascular injury and the properties of HO-1 and bilirubin are discussed by Dr. Ishikawa [2]. Down-regulation of HO-1 is an important tool for establishing the role of this protein in physiological and pathological situations. This can be achieved using molecular biology techniques as most drugs inhibiting HO-1 activity, such as metalloporphyrins, present a limited selectivity. Up-regulation of HO-1 either by targeted gene transfer or by pharmacological means is a promising therapeutic strategy in a number of disorders due to the cytoprotective properties of this enzyme. Understanding the molecular mechanisms involved in HO-1 transcription and translation is the first step for effectively controlling HO-1 expression. In the current issue Dr. Alam and Dr. Cook review [3] the interesting topic of HO-1 gene transcription, which provides a number of targets to control HO-1 protein. Selective overexpression of HO-1 and HO-2 can be achieved by gene transfer. The potential of gene therapy for a number of human diseases such as hypertension, diabetes, cancer, neurological diseases, etc. is highlighted by the contribution of Prof. Abraham [4]. Since HO-1 effects are ascribed in part to the molecules produced by its activity, a possible therapeutic approach uses CO as a pharmacological agent. CO and NO are important mediators that share similar actions in a number of tissues. Due to lack of space, some physiopathological correlations between both molecules have not been discussed. An interesting pharmacological approach is presented by Dr. Motterlini and co-workers [5], who have investigated the potential of transition metal carbonyls as CO-releasing molecules with anti-inflammatory and cytoprotective effects. The presence of HO-1 may be part of an adaptive response against injury during inflammatory processes. Our group [6] has studied several in vitro and in vivo models to assess the contribution of mediators and establish the mechanisms involved in HO-1 protection in inflammatory disorders. This issue presents a general view of the role and interest of HO modulation in human diseases to explore therapeutic alternatives. Finally, I would like to thank all the experts who have agreed to share their experiences and views in this field for their valuable contribution. References [1] Perrella MA, Yet S-F. Role of Heme Oxygenase-1 in Cardiovascular Function. Curr Pharm Design 2003; 9(30): 2479- 2787. [2] Ishikawa K. Heme Oxygenase-1 Against Vascular Insufficiency: Roles of Atherosclerotic Disorders. Curr Pharm Design 2003; 9(30): 2489-2497. [3] Alam J, Cook JL. Transcriptional Regulation of the Heme Oxygenase-1 Gene Via the Stress Response Element Pathway. Curr Pharm Design 2003; 9(30): 2499-2511. [4] Abraham NG. Therapeutic Applications of Human Heme Oxygenase Gene Transfer and Gene Therapy. Curr Pharm Design 2003; 9(30): 2513-2524. [5] Motterlini R, Mann BE, Johnson TR, Clark JE, Foresti R, Green CJ. Bioactivity and Pharmacological Actions of Carbon Monoxide-Releasing Molecules. Curr Pharm Design 2003; 9(30): 2525-2539. [6] Alcaraz MJ, Fernandez P, Guillen MI. Anti-Inflammatory Actions of the Heme Oxygenase-1 Pathway. Curr Pharm Design 2003; 9(30): 2541-2551.