Heme oxygenase-1 induction restores high-blood-flow-dependent remodeling and endothelial function in mesenteric arteries of old rats

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 suppresses a pro-inflammatory phenotype in monocytes and determines endothelial function and arterial hypertension in mice and humans

European Heart Journal ◽

10.1093/eurheartj/ehv544 ◽

2015 ◽

Vol 36 (48) ◽

pp. 3437-3446 ◽

Cited By ~ 41

Author(s):

Philip Wenzel ◽

Heidi Rossmann ◽

Christian Müller ◽

Sabine Kossmann ◽

Matthias Oelze ◽

...

Keyword(s):

Endothelial Function ◽

Arterial Hypertension ◽

Heme Oxygenase ◽

Heme Oxygenase 1 ◽

Inflammatory Phenotype

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Effects of Induction/Inhibition of Endogenous Heme Oxygenase-1 on Lipid Metabolism, Endothelial Function, and Atherosclerosis in Rabbits on a High Fat Diet

Journal of Pharmacological Sciences ◽

10.1254/jphs.11071fp ◽

2012 ◽

Vol 118 (1) ◽

pp. 14-24 ◽

Cited By ~ 20

Author(s):

Danan Liu ◽

Zuoyun He ◽

Lirong Wu ◽

Ying Fang

Keyword(s):

Lipid Metabolism ◽

Endothelial Function ◽

Heme Oxygenase ◽

High Fat Diet ◽

Heme Oxygenase 1 ◽

High Fat

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Preconditioning with soluble guanylate cyclase activation prevents postischemic inflammation and reduces nitrate tolerance in heme oxygenase-1 knockout mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00810.2012 ◽

2013 ◽

Vol 305 (4) ◽

pp. H521-H532 ◽

Cited By ~ 12

Author(s):

Walter Z. Wang ◽

Allan W. Jones ◽

Meifang Wang ◽

William Durante ◽

Ronald J. Korthuis

Keyword(s):

Heme Oxygenase ◽

Guanylate Cyclase ◽

Knockout Mice ◽

Soluble Guanylate Cyclase ◽

Ischemia Reperfusion ◽

Late Phase ◽

Nitrate Tolerance ◽

Mesenteric Arteries ◽

Heme Oxygenase 1 ◽

Leukocyte Rolling

Previously we have shown that, unlike wild-type mice (WT), heme oxygenase-1 knockout (HO-1−/−) mice developed nitrate tolerance and were not protected from inflammation caused by ischemia-reperfusion (I/R) when preconditioned with a H2S donor. We hypothesized that stimulation (with BAY 41-2272) or activation (with BAY 60-2770) of soluble guanylate cyclase (sGC) would precondition HO-1−/− mice against an inflammatory effect of I/R and increase arterial nitrate responses. Intravital fluorescence microscopy was used to visualize leukocyte rolling and adhesion to postcapillary venules of the small intestine in anesthetized mice. Relaxation to ACh and BAY compounds was measured on superior mesenteric arteries isolated after I/R protocols. Preconditioning with either BAY compound 10 min (early phase) or 24 h (late phase) before I/R reduced postischemic leukocyte rolling and adhesion to sham control levels and increased superior mesenteric artery responses to ACh, sodium nitroprusside, and BAY 41-2272 in WT and HO-1−/− mice. Late-phase preconditioning with BAY 60-2770 was maintained in HO-1−/− and endothelial nitric oxide synthase knockout mice pretreated with an inhibitor (dl-propargylglycine) of enzymatically produced H2S. Pretreatment with BAY compounds also prevented the I/R increase in small intestinal TNF-α. We speculate that increasing sGC activity and related PKG acts downstream to H2S and disrupts signaling processes triggered by I/R in part by maintaining low cellular Ca2+. In addition, BAY preconditioning did not increase sGC levels, yet increased the response to agents that act on reduced heme-containing sGC. Collectively these actions would contribute to increased nitrate sensitivity and vascular function.

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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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