Hmox1 (Heme Oxygenase-1) Protects Against Ischemia-Mediated Injury via Stabilization of HIF-1α (Hypoxia-Inducible Factor-1α)

Dunn, Louise L. and Kong, Stephanie M.Y. and Tumanov, Sergey and Chen, Weiyu and Cantley, James and Ayer, Anita and Maghzal, Ghassan J. and Midwinter, Robyn G. and Chan, Kim H. and Ng, Martin K.C. and Stocker, Roland (2021) Hmox1 (Heme Oxygenase-1) Protects Against Ischemia-Mediated Injury via Stabilization of HIF-1α (Hypoxia-Inducible Factor-1α). Arteriosclerosis, Thrombosis, and Vascular Biology, 41 (1). pp.317-330. ISSN 1079-5642

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OBJECTIVE: Hmox1 (heme oxygenase-1) is a stress-induced enzyme that catalyzes the degradation of heme to carbon monoxide, iron, and biliverdin. Induction of Hmox1 and its products protect against cardiovascular disease, including ischemic injury. Hmox1 is also a downstream target of the transcription factor HIF-1alpha (hypoxia-inducible factor-1alpha), a key regulator of the body's response to hypoxia. However, the mechanisms by which Hmox1 confers protection against ischemia-mediated injury remain to be fully understood. Approach and Results: Hmox1 deficient (Hmox1(-/-)) mice had impaired blood flow recovery with severe tissue necrosis and autoamputation following unilateral hindlimb ischemia. Autoamputation preceded the return of blood flow, and bone marrow transfer from littermate wild-type mice failed to prevent tissue injury and autoamputation. In wild-type mice, ischemia-induced expression of Hmox1 in skeletal muscle occurred before stabilization of HIF-1alpha. Moreover, HIF-1alpha stabilization and glucose utilization were impaired in Hmox1(-/-) mice compared with wild-type mice. Experiments exposing dermal fibroblasts to hypoxia (1% O2) recapitulated these key findings. Metabolomics analyses indicated a failure of Hmox1(-/-) mice to adapt cellular energy reprogramming in response to ischemia. Prolyl-4-hydroxylase inhibition stabilized HIF-1alpha in Hmox1(-/-) fibroblasts and ischemic skeletal muscle, decreased tissue necrosis and autoamputation, and restored cellular metabolism to that of wild-type mice. Mechanistic studies showed that carbon monoxide stabilized HIF-1alpha in Hmox1(-/-) fibroblasts in response to hypoxia. CONCLUSIONS: Our findings suggest that Hmox1 acts both downstream and upstream of HIF-1alpha, and that stabilization of HIF-1alpha contributes to Hmox1's protection against ischemic injury independent of neovascularization.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 25 Feb 2021 08:13
Last Modified: 19 Apr 2022 00:49

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