Our laboratory efforts are focused on identifying genetic components involved in the vertebrate response to lowered tissue oxygen conditions (hypoxia), delineating the molecular as well as biochemical mechanisms used by these signal transducers, and defining the role of these genetic factors in mammalian physiology. Hypoxia inducible factor 1a (HIF-1a) is a broadly expressed transcription factor that activates a number of target genes in response to hypoxia. Endothelial PAS domain protein 1 (EPAS1), also known as HIF-2a, is the second member of the PAS family that is closely related to HIF-1a and is only expressed in higher eukaryotes. HIF-2a is more restricted in its distribution and is expressed at high levels in vascular endothelial cells, glomus cells in the Organ of Zuckerkrandl, and pulmonary pneumocytes of the developing mouse. Homozygous HIF-2a knockout 129 S6/SvEvTac mice die in mid-gestation, likely as a consequence of catecholamine insufficiency and/or vascular defects.
The expression of HIF-2a in the adult is more widespread in comparison to the developing embryo. The sites of expression of HIF-2a in the adult are in areas of high oxygen consumption (skeletal muscle, heart, liver) or in organs that are exquisitely responsive to hypoxia (carotid body, adrenal gland). Using a genetic breeding strategy, we found that embryonic lethality of HIF-2a null mice could be partially prevented. The surviving mice lacking HIF-2a exhibit pathology in multiple organs despite co-localization of other HIF members suggesting that HIF members are not functionally redundant. The completely penetrant phenotype of HIF-2a null mice resembles a mitochondrial disease state and the molecular etiology involves impaired oxidative stress response due to inadequate production of major antioxidant enzymes (AOE).
Other aspects of the HIF-2a null phenotype include a global defect in hematopoiesis, the etiology of which involves inadequate production of the cytokine erythropoietin and consequently an impairment in early hematopoietic stem cell function. Other evidence that HIF-2 serves as a master regulator for erythropoietin comes from studies of eye in HIF-2a deficient mice. The eye, another site of erythropoietin production, is grossly abnormal in HIF-2a null mice. The molecular basis for this phenotype is multi-factorial and involves dysregulation of AOE, erythropoietin, and proangiogenic factors including VEGF-A.
Recently, we have identified that stress signaling conferred by HIF-2 is modulated by Sirt1, an NAD+ dependent deacetylase activated by altered redox state and nutrient deprivation that is implicated in the aging process in lower and higher eukaryotes. Our current efforts are aimed at delineating the molecular and biochemical basis for Sirt1/HIF-2 interactions as well as of other transcriptional regulators that act selectively with HIF-2. This novel connection between these two critical signaling molecules, HIF-2 and Sirt1, in mammals carries broad implications for the cellular response to stress-associated injury and possibly for the aging process.
RESEARCH INTERESTS
Enviromental stress signaling
Genetic factors affecting the mammalian hypoxic response
HIF biology
RECENT PUBLICATIONS
Bohensky J, Terkhorn SP, Freeman TA, Adams CS, Garcia JA, Shapiro IM, Srinivas V., "Regulation of autophagy in human and murine cartilage: hypoxia-inducible factor 2 suppresses chondrocyte autophagy." Arthritis Rheum, 60(5):1406-15, May 2009
Ivey KN, Sutcliffe D, Richardson J, Clyman RI, Garcia JA, Srivastava D., "Transcriptional regulation during development of the ductus arteriosus." Circ Res, 103(4):388-95, August 2008
Dioum EM, Clarke SL, Ding K, Repa JJ, Garcia JA., "HIF-2alpha-haploinsufficient mice have blunted retinal neovascularization due to impaired expression of a proangiogenic gene battery." Invest Ophthalmol Vis Sci., 49(6):2714-20, June 2008
Martin CM, Ferdous A, Gallardo T, Humphries C, Sadek H, Caprioli A, Garcia JA, Szweda LI, Garry MG, Garry DJ., "Hypoxia-inducible factor-2alpha transactivates Abcg2 and promotes cytoprotection in cardiac side population cells." Circ Res., 102(9):1075-81, March 2008
Oktay Y, Dioum E, Matsuzaki S, Ding K, Yan LJ, Haller RG, Szweda LI, Garcia JA., "Hypoxia-inducible factor 2alpha regulates expression of the mitochondrial aconitase chaperone protein frataxin." Journal of Biological Chemistry, 282(16):11750-6, April 2007
SIGNIFICANT PUBLICATIONS
Scortegagna M, Ding K, Oktay Y, Gaur A, Thurmond F, Yan LJ, Marck BT, Matsumoto AM, Shelton JM, Richardson JA, Bennett MJ, Garcia JA., "Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1-/- mice." Nature Genetics, 35/4:331-40, December 2003
Scortegagna M, Ding K, Zhang Q, Oktay Y, Bennett MJ, Bennett M, Shelton JM, Richardson JA, Moe O, Garcia JA., "HIF-2{alpha} regulates murine hematopoietic development in an erythropoietin-dependent manner." Blood, 105/8:3133-40, December 2004
Ding K, Scortegagna M, Seaman R, Birch DG, Garcia JA., "Retinal disease in mice lacking hypoxia-inducible transcription factor-2alpha." Invest Ophthalmol Vis Sci., 46(3):1010-6, March 2005
Nanduri J, Wang N, Yuan G, Khan SA, Souvannakitti D, Peng YJ, Kumar GK, Garcia JA, Prabhakar NR., "Intermittent hypoxia degrades HIF-2alpha via calpains resulting in oxidative stress: implications for recurrent apnea-induced morbidities." Proc Natl Acad Sci U S A., 106(4):1199-204, January 2009
Dioum EM, Chen R, Alexander MS, Zhang Q, Hogg RT, Gerard RD, Garcia JA., "Regulation of hypoxia-inducible factor 2alpha signaling by the stress-responsive deacetylase sirtuin 1." Science, 324(5932):1289-93, June 2009
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