Remote gene delivery of the transcription factor hypoxia-inducible factor 1 alpha (HIF-1a) protects hearts against ischemia-reperfusion injury. To understand why, we investigated gene expression profiles induced by HIF-1a gene delivery.

DNA encoding for human oxygen insensitive HIF-1a or saline as sham-treatment was injected into murine quadriceps muscle with electroporation to enhance DNA uptake. Human HIF-1a was expressed in the transfected muscle up to 8 weeks' after delivery (real-time PCR and immunohistochemistry). To elucidate the pattern of secondarily influenced genes, we performed Taqman low density array on 47 selected genes (around 30 known to be HIF-1a-regulated, the rest possibly HIF-1a-regulated; in 4-9 parallel experiments). In the transfected quadriceps muscles 8 genes were upregulated (Transforming growth factor–ß1, Cathepsin-L, Adrenomedullin, Heme oxygenase-1, Carbonic anhydrase-9, Insulin-like growth factor 2, p21, Monocyte chemoattractant protein-1), mostly with cardioprotective or angiogenic potential compared to sham-treated skeletal muscles (p < 0.05). When low density array was used in the contralateral muscle and the heart, gene expression was downregulated. In contralateral muscles 2 (Angiopoietin 1, Phosphofruktokinase L), in hearts 3 (Monocyte chemoattractant protein-1, Plasminogen activator inhibitor-1, Transforming growth factor–ß3) genes were downregulated (p < 0.05) compared with sham treatment.

In conclusion, remote delivery of DNA for HIF-1a increased mRNA-levels of pro-survival genes after HIF-1a-treatment in transfected muscles, whose profile was specific to the site of gene delivery.