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Aims The present study investigates whether the cardioprotection achieved by gene delivery of hypoxia-inducible factor-1α (HIF-1α) depends on the downstream factor haem oxygenase (HMOX)-1. Methods and results Immortalized cardiomyocytes (HL-1 cells) were transfected with HIF-1α or HMOX-1 and injured with hydrogen peroxide (H2O2), and death was evaluated by trypan blue staining. Quadriceps muscles of mice were treated with DNA for HIF-1α and HMOX-1, or sham-treated and electroporated, and 3 days later, hearts were isolated and subjected to global ischaemia and reperfusion. Some HIF-1α- and sham-treated mice received the HMOX blocker zinc deuteroporphyrin 2,4-bis-glycol (ZnBG) (n = 6–8 in each group). HL-1 cells were stimulated with bilirubin or the carbon monoxide donor CORM-2 before injury with H2O2. HL-1 cells which were transfected with HIF-1α or HMOX-1 had an increased survival to H2O2-induced injury compared with empty vector (n = 10–12 per group; P P 2O2 (P n = 11–15 in each group). Conclusion HIF-1α and HMOX-1 provided protection against H2O2-induced damage in HL-1 cells. Remote gene delivery of HIF-1α afforded cardioprotective effects. These were dependent on HMOX activity, as an HMOX blocker abolished the effects, and they were mimicked by pre-treatment with HMOX-1. Downstream to HMOX-1, bilirubin as well as carbon monoxide may be organ effectors. [ABSTRACT FROM AUTHOR]