Potential therapeutic gene for the treatment of ischemic disease: Ad2/hypoxia-inducible factor-1alpha (HIF-1)/VP16 enhances B-type natriuretic peptide gene expression via a HIF-1-responsive element.

In this issue of Molecular Pharmacology, Luo et al. (p. 1953) present a study employing a HIF-1alpha/VP16 chimera to investigate the mechanism by which this constitutively active transcription factor activates expression of brain natriuretic peptide (BNP). The results define a functional hypoxia responsive element (HRE) in the promoter of the human BNP gene and demonstrate that this HRE is necessary for HIF-1alpha/VP16-induced gene expression in human cardiomyocytes grown under normoxic conditions. Luo et al. also show that a consensus E-box DNA binding sequence is necessary for appropriate BNP regulation. Because HIF-1 is known to elicit protective and beneficial gene expression programs in many scenarios and because BNP is known to be cardioprotective, this study provides support for the therapeutic use of the chimeric HIF-1alpha/VP16 protein in coronary heart disease. However, because HIF-1alpha is a key regulatory molecule that acts upon a large number of downstream gene networks, there remains a need for further investigation. Particularly useful would be comprehensive gene expression profiling coupled with functional analysis of HIF-1alpha/VP16-regulated genes. The results of such studies will elucidate the mechanism of beneficial effects and address concerns regarding potential adverse effects of activating specific HIF-1alpha/VP16-dependent gene programs.