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Prolyl hydroxylase inhibitor treatment confers whole‐animal hypoxia tolerance
Author(s) -
Kasiganesan H.,
Sridharan V.,
Wright G.
Publication year - 2007
Publication title -
acta physiologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.591
H-Index - 116
eISSN - 1748-1716
pISSN - 1748-1708
DOI - 10.1111/j.1748-1716.2007.01676.x
Subject(s) - hypoxia inducible factors , hypoxia (environmental) , hypoxia inducible factor 1 , erythropoietin , transcription factor , biology , pharmacology , enzyme , microbiology and biotechnology , chemistry , endocrinology , biochemistry , oxygen , gene , organic chemistry
Aim: Recently a family of O 2 ‐dependent prolyl hydroxylase domain‐containing enzymes (PHD) has been identified as a cellular oxygen‐sensing mechanism. Reduced prolyl hydroxylase activity initiates a signalling cascade that includes the accumulation, as well as the activation, of hypoxia‐inducible factor (HIF‐1 α ). In turn the transcription factor HIF‐1 α , and other targets of the PHD, elicit a myriad of incompletely understood cellular responses. In these studies we have tested: (1) whether a small‐molecule prolyl hydroxylase inhibitor (PHI) can effectively activate the oxygen‐sensing pathway when administered systemically to mice, and (2) whether the activation of the PHD signalling pathway at the cellular level results in whole‐animal hypoxic tolerance. Methods: Mice received daily injections of the PHI, ethyl‐3,4 dihydroxybenzoate (EDHB, 100–250 mg kg −1 ) or vehicle. Tissue levels of HIF‐1 α and the serum levels of the HIF‐inducible gene, erythropoietin (EPO), were measured to evaluate PHD‐pathway activation. To evaluate hypoxic tolerance, the endurance and survival ability of these animals was tested in sublethal (8% O 2 ) and lethal hypoxia (5% O 2 ) respectively. Results: Systemic treatment of mice with the PHD inhibitor, EDHB, leads to elevated levels of HIF‐1 α in liver and HIF‐inducible EPO in serum, indicating activation of the cellular oxygen‐sensing pathway. Animals treated with EDHB display significantly increased viability and enhanced exercise performance in hypoxia. Conclusion: These results demonstrate a novel pharmacological strategy to induce hypoxic tolerance and are the first to demonstrate that the activation of the PHD oxygen‐sensing pathway at the cellular level is sufficient to produce a hypoxic‐tolerant phenotype at the physiological level of the whole animal.