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Aims: The present study investigates whether the cardioprotection achieved by gene delivery of hypoxia-inducible factor-1 alpha (HIF-1 alpha) depends on the downstream factor haem oxygenase (HMOX)-1.
Methods And Results: Immortalized cardiomyocytes (HL-1 cells) were transfected with HIF-1 alpha or HMOX-1 and injured with hydrogen peroxide (H(2)O(2)), and death was evaluated by trypan blue staining. Quadriceps muscles of mice were treated with DNA for HIF-1 alpha and HMOX-1, or sham-treated and electroporated, and 3 days later, hearts were isolated and subjected to global ischaemia and reperfusion. Some HIF-1 alpha- 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 H(2)O(2). HL-1 cells which were transfected with HIF-1 alpha or HMOX-1 had an increased survival to H(2)O(2)-induced injury compared with empty vector (n = 10-12 per group; P < 0.01 for both). When HMOX-1-luciferase reporter mice were treated with HIF-1 alpha in the quadriceps muscle, increased luciferase activity was found locally, but nowhere else. Mice pre-treated with HIF-1 alpha or HMOX-1 had a reduced infarct size, improved post-ischaemic function, and increased serum bilirubin (P < 0.05). ZnBG inhibited all these effects afforded by HIF-1 alpha. Stimulation of HL-1 cells with bilirubin and CORM-2 reduced cell death evoked by H(2)O(2) (P < 0.05 for both, n = 11-15 in each group).
Conclusion: HIF-1 alpha and HMOX-1 provided protection against H(2)O(2)-induced damage in HL-1 cells. Remote gene delivery of HIF-1 alpha 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.
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