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(Circulation Research. 2008;102:1075.)
© 2008 American Heart Association, Inc.

Cellular Biology

Hypoxia-Inducible Factor-2 Transactivates Abcg2 and Promotes Cytoprotection in Cardiac Side Population Cells

Cindy M. Martin, Anwarul Ferdous, Teresa Gallardo, Caroline Humphries, Hesham Sadek, Arianna Caprioli, Joseph A. Garcia, Luke I. Szweda, Mary G. Garry, Daniel J. Garry

From the Departments of Internal Medicine (C.M.M., A.F., C.H., H.S., A.C., J.A.G., M.G.G., D.J.G.), Pathology (T.G.), and Molecular Biology (D.J.G.) and Donald W. Reynolds Clinical Cardiovascular Center (D.J.G.), University of Texas Southwestern Medical Center, Dallas; Lillehei Heart Institute (C.M.M., A.F., M.G.G., D.J.G.), University of Minnesota, Minneapolis; and Oklahoma Medical Research Foundation (L.I.S.), Oklahoma City.

Correspondence to Daniel J. Garry, MD, PhD, Lillehei Heart Institute, University of Minneapolis, 420 Delaware St SE, MMC 508, Minneapolis, MN 55455. E-mail garry{at}umn.edu

Stem and progenitor cell populations occupy a specialized niche and are consequently exposed to hypoxic as well as oxidative stresses. We have previously established that the multidrug resistance protein Abcg2 is the molecular determinant of the side population (SP) progenitor cell population. We observed that the cardiac SP cells increase in number more than 3-fold within 3 days of injury. Transcriptome analysis of the SP cells isolated from the injured adult murine heart reveals increased expression of cytoprotective transcripts. Overexpression of Abcg2 results in an increased ability to consume hydrogen peroxide and is associated with increased levels of -glutathione reductase protein expression. Importantly, overexpression of Abcg2 also conferred a cell survival benefit following exposure to hydrogen peroxide. To further examine the molecular regulation of the Abcg2 gene, we demonstrated that hypoxia-inducible factor (HIF)-2 binds an evolutionary conserved HIF-2 response element in the murine Abcg2 promoter. Transcriptional assays reveal a dose-dependent activation of Abcg2 expression by HIF-2. These results support the hypothesis that Abcg2 is a direct downstream target of HIF-2 which functions with other factors to initiate a cytoprotective program for this progenitor SP cell population that resides in the adult heart.

Key Words: Abcg2 • cardiac SP • HIF-2 • oxidative stress

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