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Dunn 2021 Arterioscler Thromb Vasc Biol

From Bioblast
Publications in the MiPMap
Dunn LL, Kong SMY, Tumanov S, Chen W, Cantley J, Ayer A, Maghzal GJ, Midwinter RG, Chan KH, Ng MKC, Stocker R (2021) Hmox1 (heme oxygenase-1) protects against ischemia-mediated injury via stabilization of HIF-1α (hypoxia-inducible factor-1α). Arterioscler Thromb Vasc Biol 41:317-30.

» PMID: 33207934 Open Access

Dunn Louise L, Kong Stephanie M Y, Tumanov Sergey, Chen Weiyu, Cantley James, Ayer Anita, Maghzal Ghassan J, Midwinter Robyn G, Chan Kim H, Ng Martin K C, Stocker Roland (2021) Arterioscler Thromb Vasc Biol

Abstract: 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-1α (hypoxia-inducible factor-1α), 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.

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-1α. Moreover, HIF-1α 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-1α 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-1α in Hmox1-/- fibroblasts in response to hypoxia.

Our findings suggest that Hmox1 acts both downstream and upstream of HIF-1α, and that stabilization of HIF-1α contributes to Hmox1's protection against ischemic injury independent of neovascularization. Keywords: Amputation, Cardiovascular disease, Heme oxygenase-1, Metabolism, Peripheral vascular diseases Bioblast editor: Reiswig R O2k-Network Lab: AU Sydney Stocker R, AU Sydney Kong S

Labels: MiParea: Respiration, Genetic knockout;overexpression 

Stress:Hypoxia  Organism: Mouse  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue 

Coupling state: LEAK, OXPHOS, ET  Pathway: F, N, S, NS, ROX  HRR: Oxygraph-2k