We tested if remote gene delivery of hypoxia-inducible factor 1 alpha (HIF-1 alpha) protected hearts against induced ischemia, hypothesizing that gene delivery into skeletal muscle may lead to secretion of proteins with actions elsewhere. Murine quadriceps muscles were transfected with DNA encoding for human HIF-1 alpha, which resulted in a local, but lasting expression (mRNA and protein, where the latter had nuclear localization). Subjection of isolated hearts to global ischemia and reperfusion 1, 4, and 8 weeks after gene delivery resulted in infarct size reduction (p < 0.05). Supporting that this was due to paracrine effects, HL-1 cells treated with conditioned media from cells transfected with HIF-1 alpha or serum from HIF-1 alpha-treated mice were protected against H(2)O(2)-induced cell death (p < 0.05, respectively). The latter protection was reduced when a heme oxygenase activity blocker was used. Taqman low-density array of 47 HIF-1 alpha-regulated genes at the treatment site showed nine specific upregulations (p < 0.05). Of the corresponding proteins, PDGF-B and adrenomedullin were upregulated in the heart. HIF-1 alpha treatment induced an increased vascularization of the heart and skeletal muscle. In conclusion, remote delivery of DNA for HIF-1 alpha was cardioprotective, represented by consistent infarct size reduction, which may be due to release of paracrine factors from the transfected muscle.