Abstract
Background:
Ischemic preconditioning (IPC) is an effective procedure to protect against ischemia/reperfusion (I/R) injury. Hypoxia-inducible factor-1α (Hif-1α) is a key molecule in IPC, and roxadustat (RXD), a first-in-class prolyl hydroxylase domain-containing protein inhibitor, has been recently developed to treat anemia in patients with chronic kidney disease. Thus, we investigated whether RXD pretreatment protects against I/R injury.Methods and Results:RXD pretreatment markedly reduced the infarct size and suppressed plasma creatinine kinase activity in a murine I/R model. Analysis of oxygen metabolism showed that RXD could produce ischemic tolerance by shifting metabolism from aerobic to anaerobic respiration.
Conclusions:
RXD pretreatment may be a novel strategy against I/R injury.
Keywords:
Hypoxia-inducible factor-1α (Hif-1α); Ischemia/reperfusion injury; Roxadustat.
MeSH terms
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Animals
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Cell Respiration / drug effects
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Cells, Cultured
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Disease Models, Animal
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Enzyme Inhibitors / pharmacology*
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Glycine / analogs & derivatives*
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Glycine / pharmacology
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Hypoxia-Inducible Factor-Proline Dioxygenases / antagonists & inhibitors*
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Hypoxia-Inducible Factor-Proline Dioxygenases / metabolism
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Isoquinolines / pharmacology*
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Male
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Mice, Inbred C57BL
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Myocardial Infarction / metabolism
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Myocardial Infarction / pathology
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Myocardial Infarction / prevention & control*
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Myocardial Reperfusion Injury / metabolism
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Myocardial Reperfusion Injury / pathology
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Myocardial Reperfusion Injury / prevention & control*
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Myocytes, Cardiac / drug effects*
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Myocytes, Cardiac / metabolism
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Myocytes, Cardiac / pathology
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Signal Transduction
Substances
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Enzyme Inhibitors
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Hif1a protein, mouse
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Hypoxia-Inducible Factor 1, alpha Subunit
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Isoquinolines
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Hypoxia-Inducible Factor-Proline Dioxygenases
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Glycine
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roxadustat