| First Author | Dunn LL | Year | 2021 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 41 |
| Issue | 1 | Pages | 317-330 |
| PubMed ID | 33207934 | Mgi Jnum | J:318573 |
| Mgi Id | MGI:6860277 | Doi | 10.1161/ATVBAHA.120.315393 |
| Citation | Dunn LL, et al. (2021) Hmox1 (Heme Oxygenase-1) Protects Against Ischemia-Mediated Injury via Stabilization of HIF-1alpha (Hypoxia-Inducible Factor-1alpha). Arterioscler Thromb Vasc Biol 41(1):317-330 |
| abstractText | 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. |
