Dunn 2021 Arterioscler Thromb Vasc Biol
|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.|
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