Heme Oxygenase 1 Is Differentially Involved in Blood Flow–Dependent Arterial Remodeling

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.

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A new model of an arteriovenous fistula in chronic kidney disease in the mouse: beneficial effects of upregulated heme oxygenase-1

AJP Renal Physiology ◽

10.1152/ajprenal.00288.2015 ◽

2016 ◽

Vol 310 (6) ◽

pp. F466-F476 ◽

Cited By ~ 23

Author(s):

Lu Kang ◽

Joseph P. Grande ◽

Matthew L. Hillestad ◽

Anthony J. Croatt ◽

Michael A. Barry ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Blood Flow ◽

Kidney Disease ◽

Arteriovenous Fistula ◽

Heme Oxygenase ◽

Viral Gene ◽

Heme Oxygenase 1 ◽

Beneficial Effects ◽

Viral Gene Delivery ◽

Venous Wall

The arteriovenous fistula (AVF) is the preferred hemodialysis vascular access, but it is complicated by high failure rates and attendant morbidity. This study provides the first description of a murine AVF model that recapitulates two salient features of hemodialysis AVFs, namely, anastomosis of end-vein to side-artery to create the AVF and the presence of chronic kidney disease (CKD). CKD reduced AVF blood flow, observed as early as 3 days after AVF creation, and increased neointimal hyperplasia, venous wall thickness, thrombus formation, and vasculopathic gene expression in the AVF. These adverse effects of CKD could not be ascribed to preexisting alterations in blood pressure or vascular reactivity in this CKD model. In addition to vasculopathic genes, CKD induced potentially vasoprotective genes in the AVF such as heme oxygenase-1 (HO-1) and HO-2. To determine whether prior HO-1 upregulation may protect in this model, we upregulated HO-1 by adeno-associated viral gene delivery, achieving marked venous induction of the HO-1 protein and HO activity. Such HO-1 upregulation improved AVF blood flow and decreased venous wall thickness in the AVF. Finally, we demonstrate that the administration of carbon monoxide, a product of HO, acutely increased AVF blood flow. This study thus demonstrates: 1) the feasibility of a clinically relevant murine AVF model created in the presence of CKD and involving an end-vein to side-artery anastomosis; 2) the exacerbatory effect of CKD on clinically relevant features of this model; and 3) the beneficial effects in this model conferred by HO-1 upregulation by adeno-associated viral gene delivery.

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Akt1-Mediated Muscle Growth Promotes Blood Flow Recovery After Hindlimb Ischemia by Enhancing Heme Oxygenase-1 in Neighboring Cells

Circulation Journal ◽

10.1253/circj.cj-18-0135 ◽

2018 ◽

Vol 82 (11) ◽

pp. 2905-2912 ◽

Cited By ~ 2

Author(s):

Yoshiro Onoue ◽

Yasuhiro Izumiya ◽

Shinsuke Hanatani ◽

Toshifumi Ishida ◽

Yuichiro Arima ◽

...

Keyword(s):

Blood Flow ◽

Heme Oxygenase ◽

Muscle Growth ◽

Heme Oxygenase 1 ◽

Hindlimb Ischemia

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Heme Oxygenase-1 in Macrophages Impairs the Perfusion Recovery After Hindlimb Ischemia by Suppressing Autolysosome-Dependent Degradation of NLRP3

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.121.315805 ◽

2021 ◽

Author(s):

Yuankun Ma ◽

Liangliang Jia ◽

Yidong Wang ◽

Yongli Ji ◽

Jian Chen ◽

...

Keyword(s):

Bone Marrow ◽

Blood Flow ◽

Heme Oxygenase ◽

Tissue Damage ◽

Molecular Mechanisms ◽

Capillary Density ◽

Heme Oxygenase 1 ◽

Inflammasome Activation ◽

Hindlimb Ischemia ◽

Antiangiogenic Effect

Objective: Macrophage-mediated inflammatory response is closely associated with the neovascularization process following hindlimb ischemia. We previously demonstrated that HO-1 (heme oxygenase-1) in macrophages evoked proinflammatory reactions and tissue damage. Here, we evaluated the role played by macrophage-derived HO-1 and elucidated its underlying molecular mechanisms in perfusion recovery after hindlimb ischemia. Approach and Results: We found significant upregulation of HO-1 in mouse ischemic muscles after hindlimb ischemia surgery and with most of this expression occurring in infiltrated macrophages. Myeloid conditional HO-1-deficient mice exhibited higher perfusion recovery, evidenced by restored blood flow, motor function and attenuated tissue damage as well as increased capillary density in the gastrocnemius muscles after hindlimb ischemia, relative to littermate controls. This protective effect was accompanied by reduced nod-like receptor family, NLRP3 (pyrin domain containing 3) inflammasome activation in the infiltrated macrophages without the alteration of macrophage infiltration and polarization. Moreover, suppressing inflammasome activation with NLRP3 inhibitor MCC950 improved blood flow and capillary density in wild-type mice compared with untreated mice. Mechanistically, suppressing HO-1 abolished TNF (tumor necrosis factor)-α-induced NLRP3 protein rather than mRNA expression in bone marrow–derived macrophages, indicating that HO-1 mediated post-transcriptional regulation of NLRP3. Furthermore, HO-1 inhibition promoted autolysosome-dependent degradation of NLRP3 in bone marrow–derived macrophages. Matrigel tube formation assay revealed that HO-1 deletion abrogated the antiangiogenic effect of inflammasome-activated macrophages. Conclusions: Taken together, these findings indicate that macrophage HO-1 deficiency promotes perfusion recovery after hindlimb ischemia by accelerating autolysosomal degradation of NLRP3. The underlying mechanism of action is a potential target for therapeutic angiogenesis in ischemic diseases.

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Targeting Heme Oxygenase-1 in the Arterial Response to Injury and Disease

Antioxidants ◽

10.3390/antiox9090829 ◽

2020 ◽

Vol 9 (9) ◽

pp. 829 ◽

Cited By ~ 3

Author(s):

William Durante

Keyword(s):

Heme Oxygenase ◽

Critical Role ◽

Vascular Diseases ◽

Phenotypic Switching ◽

Heme Oxygenase 1 ◽

Bile Pigments ◽

Arterial Remodeling ◽

Pulmonary Arterial ◽

Or Gene ◽

Transplant Arteriosclerosis

Heme oxygenase-1 (HO-1) catalyzes the degradation of heme into carbon monoxide (CO), iron, and biliverdin, which is rapidly metabolized to bilirubin. The activation of vascular smooth muscle cells (SMCs) plays a critical role in mediating the aberrant arterial response to injury and a number of vascular diseases. Pharmacological induction or gene transfer of HO-1 improves arterial remodeling in animal models of post-angioplasty restenosis, vascular access failure, atherosclerosis, transplant arteriosclerosis, vein grafting, and pulmonary arterial hypertension, whereas genetic loss of HO-1 exacerbates the remodeling response. The vasoprotection evoked by HO-1 is largely ascribed to the generation of CO and/or the bile pigments, biliverdin and bilirubin, which exert potent antioxidant and anti-inflammatory effects. In addition, these molecules inhibit vascular SMC proliferation, migration, apoptosis, and phenotypic switching. Several therapeutic strategies are currently being pursued that may allow for the targeting of HO-1 in arterial remodeling in various pathologies, including the use of gene delivery approaches, the development of novel inducers of the enzyme, and the administration of unique formulations of CO and bilirubin.

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I022 Role of heme oxygenase-1 in high blood flow (shear stress)-induced remodeling of rat resistance arteries

Archives of Cardiovascular Diseases ◽

10.1016/s1875-2136(09)72356-3 ◽

2009 ◽

Vol 102 ◽

pp. S94

Author(s):

M.-L. Freidja ◽

E. Vessieres ◽

B. Toutain ◽

L. Loufrani ◽

S. Faure ◽

...

Keyword(s):

Blood Flow ◽

Shear Stress ◽

Heme Oxygenase ◽

Heme Oxygenase 1 ◽

Resistance Arteries ◽

Flow Shear ◽

Flow Shear Stress

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HEME OXYGENASE-1 GENE THERAPY FOR PREVENTION OF VASOSPASM IN RATS

Stroke ◽

10.1161/str.32.suppl_1.330 ◽

2001 ◽

Vol 32 (suppl_1) ◽

pp. 330-330

Author(s):

Robert L Macdonald Dr. ◽

Shigeki Ono Dr.

Keyword(s):

Blood Flow ◽

Heme Oxygenase ◽

Basilar Artery ◽

Cerebral Arteries ◽

Heme Oxygenase 1 ◽

Mrna Levels ◽

Messenger Ribonucleic Acid ◽

Cisterna Magna ◽

Protein Levels ◽

Vehicle Injection

78 This study tested the hypothesis that adenovirus expressing heme oxygenase-1 (HO-1), the enzyme that metabolises hemoglobin, would reduce contractions of cerebral arteries to hemoglobin and decrease vasospasm after subarachnoid hemorrhage (SAH). Rats underwent injection of vehicle or replication defective adenovirus expressing HO-1 (Ad5HO-1) or β-galactosidase (Ad-βGal) into the cisterna magna. Transgene expression was assessed by reverse transcriptase polymerase chain reaction for messenger ribonucleic acid (mRNA) levels, immunoblotting for protein levels, immunohistochemistry, response of the basilar artery to pure, ferrous hemoglobin and carboxyhemoglobin production 1 day after virus injection. Effects of Ad5HO-1 and Ad-βGal on vasospasm were assessed in a rat double hemorrhage model. Injection of Ad5HO-1 significantly increased HO-1 mRNA, protein and activity in basilar artery compared to Ad-βGal and vehicle. Injection of Ad-βGal result in low level expression and activity of HO-1 but this was significantly less than after injection of Ad5HO-1. HO-1 immunoreactivity was present in the basilar artery adventitia after injection of Ad5HO-1 and Ad-βGal. Injection of Ad5HO-1 and Ad-βGal increased basilar artery diameter and brainstem blood flow compared to control (P < 0.001, ANOVA). Ad5HO-1, however, significantly and selectively prevented contraction of the basilar artery and reduction in brainstem cerebral blood flow due to hemoglobin and significantly increased carboxyhemoglobin concentration compared to Ad-βGal and vehicle. Basilar artery diameter 7 days after SAH was significantly greater after injection of Ad5HO-1 (380 ± 36 μm) compared to Ad-βGal (282 ± 44 μm) and vehicle (287 ± 31μm, P < 0.001, ANOVA). In conclusion, injection of Ad5HO-1 into the cisterna magna of rats results in expression of functional HO-1 in the adventitia of the basilar artery. This is associated with an increase in basilar artery diameter. HO-1 expression with Ad5HO-1 inhibits arterial contractions to hemoglobin and after SAH.

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