Anemia, a common condition in Veteran patients, is a potent risk factor for increased morbidity and mortality when accompanying other disease states. Although therapies for anemia have improved over the past several decades, almost all current therapies involve bolus administration of erythropoietin (epo), an endocrine factor produced in the adult kidney and also in the liver with severe anemia. Non-physiological, bolus epo administration has untoward effects, including a possible increased thrombotic risk as well as an undesirable stimulatory effect on cancer. Understanding how epo is regulated will allow investigators to develop rational therapies besides epo replacement. Our current focus is defining molecular mechanisms regulating epo expression in mammals. Hypoxia Inducible Factor (HIF) transcription factors are a family of molecular mediators that induce the protective cellular response to hypoxia. We were the first to establish that the second HIF member, HIF-2, is critical for in vivo epo gene expression. While an essential role of HIF-2 in epo regulation is now recognized, the factors responsible for temporal epo gene expression in vivo, or for abnormal repression of epo gene expression in anemia patients, remain poorly understood. We recently identified a novel mechanism of HIF-2 signaling that affects epo regulation. Activity of HIF-1, the founding HIF member, is controlled predominantly by changes in protein levels, which is mediated by oxygen-dependent post-translational modifications of the HIF-1 protein. However, although the HIF-2 protein undergoes the same oxygen-dependent post-translational modifications, this mechanism is not the sole or even major mechanism for controlling HIF-2 signaling. If not the lack of oxygen, what then is the molecular trigger for activating HIF-2? Our central hypothesis is that hypoxia triggers changes in intermediary metabolism to effect acetylation of HIF-2. In Preliminary Data, we show that HIF-2 activity is controlled by two post-translational modifications, acetylation and deacetylation. In Pilot Studies, we identify the molecular and biochemical basis for HIF-2 acetylation, termed the acetate switch, which involves changes in intermediary metabolism to induce HIF-2 acetylation and coactivator recruitment. Deciphering how the acetate switch regulates HIF-2 signaling will provide novel insights into normal epo regulation and will identify selective molecular targets for modulation of endogenous epo gene expression in patients with anemia.

Public Health Relevance

Anemia results in worse outcomes for patients requiring critical care unit services. Unfortunately, acute treatment of anemia with bolus erythropoietin (epo) does not improve outcomes. The transcription factor Hypoxia Inducible Factor 2 (HIF-2) regulates epo expression in mammals. Our underlying premise is that HIF-2 signaling does not function properly in a subset of anemia patients. Our hope is that by restoring normal HIF-2 signaling, epo regulation can be regulated by normal physiological mechanisms. To assess if this is true, we first need to understand the way in which HIF-2 signaling is activated in normal individuals. We have recently identified a novel mechanism to control HIF-2 signaling. In this proposal, we will further our understanding of this mechanism and we will determine if this mechanism operates in mammals. The Potential Impact on Veterans Health Care is preventing the development and progression of anemia, a major and prevalent co-morbid condition in veterans.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000446-07
Application #
8963422
Study Section
Hematology (HEMA)
Project Start
2009-04-01
Project End
2016-09-30
Budget Start
2015-10-01
Budget End
2016-09-30
Support Year
7
Fiscal Year
2016
Total Cost
Indirect Cost
Name
VA North Texas Health Care System
Department
Type
DUNS #
007369325
City
Dallas
State
TX
Country
United States
Zip Code
75216
Kimura, Wataru; Xiao, Feng; Canseco, Diana C et al. (2015) Hypoxia fate mapping identifies cycling cardiomyocytes in the adult heart. Nature 523:226-30
Chen, Rui; Xu, Min; Nagati, Jason S et al. (2015) The acetate/ACSS2 switch regulates HIF-2 stress signaling in the tumor cell microenvironment. PLoS One 10:e0116515
Xu, Min; Nagati, Jason S; Xie, Jian et al. (2014) An acetate switch regulates stress erythropoiesis. Nat Med 20:1018-26
Puente, Bao N; Kimura, Wataru; Muralidhar, Shalini A et al. (2014) The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response. Cell 157:565-79
Yuan, Guoxiang; Peng, Ying-Jie; Reddy, Vaddi Damodara et al. (2013) Mutual antagonism between hypoxia-inducible factors 1? and 2? regulates oxygen sensing and cardio-respiratory homeostasis. Proc Natl Acad Sci U S A 110:E1788-96
Scheuermann, Thomas H; Li, Qiming; Ma, He-Wen et al. (2013) Allosteric inhibition of hypoxia inducible factor-2 with small molecules. Nat Chem Biol 9:271-6
Chen, Rui; Xu, Min; Hogg, Richard T et al. (2012) The acetylase/deacetylase couple CREB-binding protein/Sirtuin 1 controls hypoxia-inducible factor 2 signaling. J Biol Chem 287:30800-11
Kocabas, Fatih; Mahmoud, Ahmed I; Sosic, Drazen et al. (2012) The hypoxic epicardial and subepicardial microenvironment. J Cardiovasc Transl Res 5:654-65
Banerjee, Subhash; Xu, Hao; Fuh, Eric et al. (2012) Endothelial progenitor cell response to antiproliferative drug exposure. Atherosclerosis 225:91-8
Peng, Ying-Jie; Nanduri, Jayasri; Khan, Shakil A et al. (2011) Hypoxia-inducible factor 2? (HIF-2?) heterozygous-null mice exhibit exaggerated carotid body sensitivity to hypoxia, breathing instability, and hypertension. Proc Natl Acad Sci U S A 108:3065-70

Showing the most recent 10 out of 17 publications