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A Constitutively Active Hypoxia-Inducible Factor-1/VP16 Hybrid Factor Activates Expression of the Human B-Type Natriuretic Peptide Gene

Genzyme Corporation, Framingham, Massachusetts

Hypoxia-inducible factor-1 (HIF-1) is a primary regulator of the physiological response to hypoxia. A recombinant adenovirus expressing a constitutively active hybrid form of the HIF-1 subunit (Ad2/HIF-1/VP16) is being evaluated as a gene therapy for the treatment of peripheral vascular disease. Ad2/HIF-1/VP16 up-regulates known HIF-1-responsive genes, including those involved in angiogenesis. Expression profile analysis revealed that the brain natriuretic peptide (BNP) gene was significantly up-regulated in response to HIF-1/VP16 in human fetal cardiac cells. Real-time reverse transcription-polymerase chain reaction analyses confirmed transcriptional activation of the BNP gene by HIF-1/VP16 in human but not rat cardiac cells. Because hypoxia itself did not increase human BNP gene expression in these analyses, the mechanism of the HIF-1/VP16 effect was determined. Analyses of promoter deletion mutants suggested that the cis-acting sequence in the human BNP promoter mediating activation by HIF-1/VP16 was a putative HIF-1 responsive element (HRE) located at -466. An SV40 basal promoter-luciferase plasmid containing a minimal BNP HRE was up-regulated by HIF-1/VP16, whereas a similar construct carrying a mutation within the HIF-1 binding site was not. Mutation of an E-box motif within the BNP HRE reduced HIF-1/VP16-mediated transcriptional activation by 50%. Gel-shift analyses showed that both the native HIF-1 and HIF-1/VP16 are able to bind to a probe containing the HIF-1 binding site. These experiments demonstrate the existence of a functional HRE in the BNP promoter and further define the scope and mechanism of action of Ad2/HIF-1/VP16.

Received for publication August 18, 2005.

Accepted for publication February 28, 2006.

Address correspondence to: Dr. Karen A. Vincent, Genzyme Corporation, 31 New York Ave, P.O. Box 9322, Framingham, MA 01701-9322. E-mail: karen.vincent{at}genzyme.com

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