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A Systems Model of HIF1α Dynamics in Ischemia
Author(s) -
Qutub Amina Ann,
Popel Aleksander S.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.767.6
Subject(s) - angiogenesis , ischemia , inflammation , hypoxia (environmental) , microbiology and biotechnology , hypoxia inducible factors , transcription factor , glycolysis , signal transduction , pharmacology , biology , chemistry , immunology , cancer research , medicine , biochemistry , metabolism , gene , oxygen , organic chemistry
During ischemia, a cell responds to changing oxygen levels by activation of a transcription factor, hypoxia‐inducible factor 1 (HIF1). HIF1, in response to hypoxia, upregulates genes involved in angiogenesis, cell growth, glycolysis and inflammation. To characterize this process, we used computational modeling to predict HIF1 signaling during ischemia, on multiple biological levels. We developed models based on extensive published experimental data on HIF1α in different microenvironments. Three intracellular models consist of ordinary differential equations that represent HIF1α hydroxylation, succinate product inhibition and reactive oxygen species effects. We also designed an experimentally‐based network model of HIF1α signaling pathways related to inflammation and angiogenesis; this model includes HIF1 modulation by NFκB, TGFβ, VEGF, and insulin. Finally, we developed a cellular rule‐based model that relates hypoxia to blood vessel formation. In these models, we studied the conditions of hypoxia and ischemia, for different durations. Model results predict relative expression of HIF1α in ischemic environments, intracellularly and at the tissue level. Results suggest an optimal window for therapeutic intervention following the onset of ischemia; during this time, inflammatory response could be minimized, while angiogenesis would still occur. This window depends on levels of HIF1α and H 2 O 2 intracellularly, and the modulation of signaling responses in adjacent cells and tissue. In stroke, peripheral artery disease or wound‐healing, minimizing inflammation while maximizing angiogenesis is a means to restore health. The combined HIF1 systems models predict how this can be achieved through regulation of hypoxic pathways.