Hypoxia-inducible factor-2alpha transactivates Abcg2 and promotes cytoprotection in cardiac side population cells.
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 alpha-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)-2alpha binds an evolutionary conserved HIF-2alpha response element in the murine Abcg2 promoter. Transcriptional assays reveal a dose-dependent activation of Abcg2 expression by HIF-2alpha. These results support the hypothesis that Abcg2 is a direct downstream target of HIF-2alpha which functions with other factors to initiate a cytoprotective program for this progenitor SP cell population that resides in the adult heart.
Martin
Cindy M
CM
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA.
Ferdous
Anwarul
A
Gallardo
Teresa
T
Humphries
Caroline
C
Sadek
Hesham
H
Caprioli
Arianna
A
Garcia
Joseph A
JA
Szweda
Luke I
LI
Garry
Mary G
MG
Garry
Daniel J
DJ
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D053687:Adult Stem Cells / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D003080:Cold Temperature / Q000009:adverse effects; D019610:Cytoprotection / Q000235:genetics; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling / Q000379:methods; D005980:Glutathione Reductase / Q000378:metabolism; D006335:Heart Injuries / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006861:Hydrogen Peroxide / Q000378:metabolism; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D015854:Up-Regulation; D000099162:Endothelial PAS Domain-Containing Protein 1
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D051792:Basic Helix-Loop-Helix Proteins; D005980:Glutathione Reductase; D006861:Hydrogen Peroxide; D012333:RNA, Messenger; D000099162:Endothelial PAS Domain-Containing Protein 1; C501412:Abcg2 protein, mouse