Hypoxia inducible factor pathways as targets for functional foods.

The etiology of most chronic angiogenic diseases such as rheumatoid arthritis, atherosclerosis, diabetes complications, and cancer includes the presence of pockets of hypoxic cells growing behind aerobic cells and away from blood vessels. Hypoxic cells are the result of uncontrolled growth and insufficient vascularization and have undergone a shift from aerobic to anaerobic metabolism. Cells respond to hypoxia by stimulating the expression of hypoxia inducible factor (HIF), which is critical for survival under hypoxic conditions and in embryogenesis. HIF is a heterodimer consisting of the O2-regulated subunit, HIF-1alpha, and the constitutively expressed aryl hydrocarbon receptor nuclear translocator, HIF-1beta. Under hypoxic conditions, HIF-1alpha is stable, accumulates, and migrates to the nucleus where it binds to HIF-1beta to form the complex (HIF-1alpha + HIF-1beta). Transcription is initiated by the binding of the complex (HIF-1alpha + HIF-1beta) to hypoxia responsive elements (HREs). The complex [(HIF-1alpha + HIF-1beta) + HREs] stimulates the expression of genes involved in angiogenesis, anaerobic metabolism, vascular permeability, and inflammation. Experimental and clinical evidence show that these hypoxic cells are the most aggressive and difficult angiogenic disease cells to treat and are a major reason for antiangiogenic and conventional treatment failure. Hypoxia occurs in early stages of disease development (before metastasis), activates angiogenesis, and stimulates vascular remodeling. HIF-1alpha has also been identified under aerobic conditions in certain types of cancer. This review summarizes the role of hypoxia in some chronic degenerative angiogenic diseases and discusses potential functional foods to target the HIF-1alpha pathways under hypoxic and normoxic conditions. It is reported that dietary quinones, semiquinones, phenolics, vitamins, amino acids, isoprenoids, and vasoactive compounds can down-regulate the HIF-1 pathways and therefore the expression of several proangiogenic factors. Considering the lack of efficiency or the side effects of synthetic antiangiogenic drugs at clinical trials, down-regulation of hypoxia-induced angiogenesis by use of naturally occurring functional foods may provide an effective means of prevention.