Hypoxia-inducible Factor 1 Alpha as a Cardioprotective Agent

摘要

Hypoxia-inducible factor 1 alpha (HIF-1alpha) is a transcription factor regulating cellular responses to hypoxia. Upon activation it will translocate to the nucleus and initiate transcription of genes involved in angiogenesis, oxygen uptake and transport, glucose metabolism, iron metabolism, vascular tone, and regulation of cell cycle and survival. HIF-lalpha gene therapy directly in ischemic tissue improves organ survival. We wanted to establish a clinically easily accessible route of gene transfer, and hypothetized that delivery of DNA encoding for HIF-1alpha into skeletal muscle would lead to formation of secretory proteins which in an endocrine manner could protect remote organs such as the ischemic heart. Delivery of DNA encoding for HIF-1alpha to mouse quadriceps muscle and enhancing nuclear uptake through electroporation reduces ischemic injury to the heart ex vivo and in vivo, and protects the cardiomyocyte HL-1 cell line against injury. Remote genetic cardioprotection may become a therapeutic option.