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

Abstract

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-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. 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-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% O 2 ) 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. Conclusions: 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.

WITHDRAWN: Remifentanil preconditioning alleviates myocardial ischemia/reperfusion injury in rats via activating Jagged-1/Notch signaling pathway

“…Furthermore, remifentanil preconditioning led to a remarkable increase in HIF-1 level the cardiac tissues. Notably, recent studies have revealed that elevated HIF-1 could protect the organs from I/R-induced damage through potentiating antioxidant activity and facilitating cell survival [37][38][39]. Besides, cell model experiments showed that remifentanil preconditioning significantly reversed the increase in intracellular ROS accumulation and apoptosis of H9c2 cardiomyocytes triggered by hypoxia/reoxygenation exposure.…”

Crosstalk Between Dysfunctional Mitochondria and Inflammation in Glaucomatous Neurodegeneration

“…The precise mechanism remains to be determined, although action on KCa 2+ channels in the outflow pathway has been suggested ( Dong et al, 2007 ; Bucolo and Drago, 2011 ). Recent work in a model of hind limb ischemia suggests the stabilization of HIF-1α by hemeoxygenase 1 (Hmox1) is at least partially attributed to carbon monoxide, with carbon monoxide a by-product of the breakdown of heme by of Hmox1 ( Dunn et al, 2021 ). In addition, carbon monoxide regulates mitochondrial biogenesis and gene expression, suggesting multiple protective sites in glaucoma are possible ( Cherry and Piantadosi, 2015 ).…”

Targeting the Ang2/Tie2 Axis with Tanshinone IIA Elicits Vascular Normalization in Ischemic Injury and Colon Cancer

“…Of note, the endogenous neovascularization mediated by high blood pressure and shear stress was frequently lack of lumen, and it thus might not be effectively involved in the blood circulation in the ischemic tissues [ 22 ]. The sustained hypoxia was responsible for failure of muscle recovery, extensive tissue necrosis, and severe muscle mass loss [ 23 ]. As shown in Figures 1(e) and 1(f) , the ischemic hind limbs of the mice in the model group presented the phenotypes of muscle fiber degeneration, necrosis, inflammation, and calcification, which could be rescued by 30 and 90 mg/kg of Tan IIA.…”