Regulation of heme oxygenase-1 expression in vivo and in vitro in hyperoxic lung injury.

1996 ◽  
Vol 14 (6) ◽  
pp. 556-568 ◽  
Author(s):  
P J Lee ◽  
J Alam ◽  
S L Sylvester ◽  
N Inamdar ◽  
L Otterbein ◽  
...  
Keyword(s):  
Lung Injury ◽  
Heme Oxygenase ◽  
Heme Oxygenase 1 ◽  
Hyperoxic Lung Injury

scholarly journals Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models

2021 ◽  
Vol 22 (4) ◽  
pp. 1514 ◽  
Author(s):  
Akihiro Yachie
Keyword(s):  
Oxidative Stress ◽  
Animal Models ◽  
Heme Oxygenase ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Pharmacological Intervention ◽  
Heme Oxygenase 1 ◽  
Inflammatory Reactions

Since Yachie et al. reported the first description of human heme oxygenase (HO)-1 deficiency more than 20 years ago, few additional human cases have been reported in the literature. A detailed analysis of the first human case of HO-1 deficiency revealed that HO-1 is involved in the protection of multiple tissues and organs from oxidative stress and excessive inflammatory reactions, through the release of multiple molecules with anti-oxidative stress and anti-inflammatory functions. HO-1 production is induced in vivo within selected cell types, including renal tubular epithelium, hepatic Kupffer cells, vascular endothelium, and monocytes/macrophages, suggesting that HO-1 plays critical roles in these cells. In vivo and in vitro studies have indicated that impaired HO-1 production results in progressive monocyte dysfunction, unregulated macrophage activation and endothelial cell dysfunction, leading to catastrophic systemic inflammatory response syndrome. Data from reported human cases of HO-1 deficiency and numerous studies using animal models suggest that HO-1 plays critical roles in various clinical settings involving excessive oxidative stress and inflammation. In this regard, therapy to induce HO-1 production by pharmacological intervention represents a promising novel strategy to control inflammatory diseases.

Heme oxygenase-1 induction by hemin prevents oxidative stress-induced acute cholestasis in the rat

2019 ◽  
Vol 133 (1) ◽  
pp. 117-134 ◽  
Author(s):  
Pamela L. Martín ◽  
Paula Ceccatto ◽  
María V. Razori ◽  
Daniel E.A. Francés ◽  
Sandra M.M. Arriaga ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heme Oxygenase ◽  
Bile Flow ◽  
Driving Forces ◽  
Membrane Lipids ◽  
Ex Vivo ◽  
Heme Oxygenase 1 ◽  
Canalicular Transporters

Abstract We previously demonstrated in in vitro and ex vivo models that physiological concentrations of unconjugated bilirubin (BR) prevent oxidative stress (OS)-induced hepatocanalicular dysfunction and cholestasis. Here, we aimed to ascertain, in the whole rat, whether a similar cholestatic OS injury can be counteracted by heme oxygenase-1 (HO-1) induction that consequently elevates endogenous BR levels. This was achieved through the administration of hemin, an inducer of HO-1, the rate-limiting step in BR generation. We found that BR peaked between 6 and 8 h after hemin administration. During this time period, HO-1 induction fully prevented the pro-oxidant tert-butylhydroperoxide (tBuOOH)-induced drop in bile flow, and in the biliary excretion of bile salts and glutathione, the two main driving forces of bile flow; this was associated with preservation of the membrane localization of their respective canalicular transporters, bile salt export pump (Bsep) and multidrug resistance-associated protein 2 (Mrp2), which are otherwise endocytosed by OS. HO-1 induction counteracted the oxidation of intracellular proteins and membrane lipids induced by tBuOOH, and fully prevented the increase in the oxidized-to-total glutathione (GSHt) ratio, a sensitive parameter of hepatocellular OS. Compensatory elevations of the activity of the antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD) were also prevented. We conclude that in vivo HO-1 induction protects the liver from acute oxidative injury, thus preventing consequent cholestasis. This reveals an important role for the induction of HO-1 and the consequently elevated levels of BR in preserving biliary secretory function under OS conditions, thus representing a novel therapeutic tool to limit the cholestatic injury that bears an oxidative background.

Kaposi sarcoma-associated herpesvirus (KSHV) induces heme oxygenase-1 expression and activity in KSHV-infected endothelial cells

Blood ◽  
2004 ◽  
Vol 103 (9) ◽  
pp. 3465-3473 ◽  
Author(s):  
Shane C. McAllister ◽  
Scott G. Hansen ◽  
Rebecca A. Ruhl ◽  
Camilo M. Raggo ◽  
Victor R. DeFilippis ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Heme Oxygenase ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Kaposi Sarcoma ◽  
Heme Oxygenase 1 ◽  
Spindle Cell Proliferation

Abstract Kaposi sarcoma (KS) is the most common AIDS-associated malignancy and is characterized by angiogenesis and the presence of spindle cells. Kaposi sarcoma-associated herpesvirus (KSHV) is consistently associated with all clinical forms of KS, and in vitro infection of dermal microvascular endothelial cells (DMVECs) with KSHV recapitulates many of the features of KS, including transformation, spindle cell proliferation, and angiogenesis. To study the molecular mechanisms of KSHV pathogenesis, we compared the protein expression profiles of KSHV-infected and uninfected DMVECs. This comparison revealed that heme oxygenase-1 (HO-1), the inducible enzyme responsible for the rate-limiting step in heme catabolism, was up-regulated in infected endothelial cells. Recent evidence suggests that the products of heme catabolism have important roles in endothelial cell biology, including apoptosis and angiogenesis. Here we show that HO-1 mRNA and protein are up-regulated in KSHV-infected cultures. Comparison of oral and cutaneous AIDS-KS tissues with normal tissues revealed that HO-1 mRNA and protein were also up-regulated in vivo. Increased HO-1 enzymatic activity in vitro enhanced proliferation of KSHV-infected DMVECs in the presence of free heme. Treatment with the HO-1 inhibitor chromium mesoporphyrin IX abolished heme-induced proliferation. These data suggest that HO-1 is a potential therapeutic target for KS that warrants further study. (Blood. 2004;103: 3465-3473)

scholarly journals Alleviation of Cartilage Destruction by Sinapic Acid in Experimental Osteoarthritis

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Dawei Cai ◽  
Thomas W. Huff ◽  
Jun Liu ◽  
Tangbo Yuan ◽  
Zijian Wei ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Nuclear Translocation ◽  
Sinapic Acid ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Transactivation Activity ◽  
Nrf2 Signaling Pathway ◽  
Primary Mouse

Sinapic acid (SA) modulates the nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathway in chondrocytes. In order to test the hypothesis that SA is protective against the development of osteoarthritis (OA), primary mouse chondrocytes were treated in vitro with SA and the promoter transactivation activity of heme oxygenase 1 (HO-1), nuclear translocation of Nrf2, and protein expression of HO-1 were assayed. To test the hypothesis in vivo, a destabilization of the medial meniscus (DMM) model was used to induce OA in the knees of mice and SA was delivered orally to the experimental group. The chondrocytes were harvested for further analysis. The expression of HO-1 was similarly upregulated in cartilage from both the experimental mice and human chondrocytes from osteoarthritic knees. SA was found to enhance the promoter transactivation activity of heme oxygenase 1 (HO-1) and increase the expression of Nrf2 and HO-1 in primary chondrocytes. Histopathologic scores showed that the damage induced by the DMM model was significantly lower in the SA treatment group. The addition of a HO-1 inhibitor with SA did not show additional benefit over SA alone in terms of cartilage degradation or histopathologic scores. The expression of TNF-α, IL-1β, IL-6, MMP-1, MMP-3, MMP-13, ADAMTS4, and ADAMTS5 was significantly reduced both in vitro and in vivo by the presence of SA. Protein expressions of HO-1 and Nrf2 were substantially increased in knee cartilage of mice that received oral SA. Our results suggest that SA should be further explored as a preventative treatment for OA.

scholarly journals Heme Oxygenase-1, a Key Enzyme for the Cytoprotective Actions of Halophenols by Upregulating Nrf2 Expression via Activating Erk1/2 and PI3K/Akt in EA.hy926 Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Xiu E. Feng ◽  
Tai Gang Liang ◽  
Jie Gao ◽  
De Peng Kong ◽  
Rui Ge ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Antioxidant Activities ◽  
Heme Oxygenase 1 ◽  
Protective Effects ◽  
Key Enzyme ◽  
Ea.Hy926 Cells ◽  
Anti Inflammatory ◽  
Mechanistic Basis

Increasing evidence has demonstrated that heme oxygenase-1 (HO-1) is a key enzyme triggered by cellular stress, exhibiting cytoprotective, antioxidant, and anti-inflammatory abilities. Previously, we prepared a series of novel active halophenols possessing strong antioxidant activities in vitro and in vivo. In the present study, we demonstrated that these halophenols exhibited significant protective effects against H2O2-induced injury in EA.hy926 cells by inhibition of apoptosis and ROS and TNF-αproduction, as well as induction of the upregulation of HO-1, the magnitude of which correlated with their cytoprotective actions. Further experiments which aimed to determine the mechanistic basis of these actions indicated that the halophenols induced the activation of Nrf2, Erk1/2, and PI3K/Akt without obvious effects on the phosphorylation of p38, JNK, or the expression of PKC-δ. This was validated with the use of PD98059 and Wortmannin, specific inhibitors of Erk1/2 and PI3K, respectively. Overall, our study is the first to demonstrate that the cytoprotective actions of halophenols involve their antiapoptotic, antioxidant, and anti-inflammatory abilities, which are mediated by the upregulation of Nrf2-dependent HO-1 expression and reductions in ROS and TNF-αgeneration via the activation of Erk1/2 and PI3K/Akt in EA.hy926 cells. HO-1 may thus be an important potential target for further research into the cytoprotective actions of halophenols.

Expression Profiling of microRNAs Related to Heme Oxygenase−1 in a Mouse Model of Hyperoxic Lung Injury

2013 ◽  
Vol 65 ◽  
pp. S158-S159
Author(s):  
Hayato Go ◽  
Ping La ◽  
Fumihiko Namba ◽  
Patrick Amal Fernando ◽  
Guang Yang ◽  
...  
Keyword(s):  
Lung Injury ◽  
Mouse Model ◽  
Heme Oxygenase ◽  
Expression Profiling ◽  
Heme Oxygenase 1 ◽  
Hyperoxic Lung Injury

scholarly journals Heme Oxygenase-1 Mediates Neuroprotection Conferred by Argon in Combination with Hypothermia in Neonatal Hypoxia–Ischemia Brain Injury

2016 ◽  
Vol 125 (1) ◽  
pp. 180-192 ◽  
Author(s):  
Hailin Zhao ◽  
Sian Mitchell ◽  
Stefania Koumpa ◽  
Yushi Tracy Cui ◽  
Qingquan Lian ◽  
...  
Keyword(s):  
Brain Injury ◽  
Heme Oxygenase ◽  
Glycogen Synthase ◽  
Glucose Deprivation ◽  
In Vivo Studies ◽  
Heme Oxygenase 1 ◽  
Hypothermia Treatment ◽  
Hypoxia Ischemia

Abstract Background Hypoxic–ischemic encephalopathy is a major cause of mortality and disability in the newborn. The authors investigated the protective effects of argon combined with hypothermia on neonatal rat hypoxic–ischemic brain injury. Methods In in vitro studies, rat cortical neuronal cell cultures were challenged by oxygen and glucose deprivation for 90 min and exposed to 70% Ar or N2 with 5% CO2 balanced with O2, at 33°C for 2 h. Neuronal phospho-Akt, heme oxygenase-1 and phospho-glycogen synthase kinase-3β expression, and cell death were assessed. In in vivo studies, neonatal rats were subjected to unilateral common carotid artery ligation followed by hypoxia (8% O2 balanced with N2 and CO2) for 90 min. They were exposed to 70% Ar or N2 balanced with oxygen at 33°, 35°, and 37°C for 2 h. Brain injury was assessed at 24 h or 4 weeks after treatment. Results In in vitro studies, argon–hypothermia treatment increased phospho-Akt and heme oxygenase-1 expression and significantly reduced the phospho-glycogen synthase kinase-3β Tyr-216 expression, cytochrome C release, and cell death in oxygen–glucose deprivation–exposed cortical neurons. In in vivo studies, argon–hypothermia treatment decreased hypoxia/ischemia-induced brain infarct size (n = 10) and both caspase-3 and nuclear factor-κB activation in the cortex and hippocampus. It also reduced hippocampal astrocyte activation and proliferation. Inhibition of phosphoinositide-3-kinase (PI3K)/Akt pathway through LY294002 attenuated cerebral protection conferred by argon–hypothermia treatment (n = 8). Conclusion Argon combined with hypothermia provides neuroprotection against cerebral hypoxia–ischemia damage in neonatal rats, which could serve as a new therapeutic strategy against hypoxic–ischemic encephalopathy.

scholarly journals PGC1α Regulates the Endothelial Response to Fluid Shear Stress via Telomerase Reverse Transcriptase Control of Heme Oxygenase-1

2021 ◽  
Author(s):  
Shashi Kant ◽  
Khanh-Van Tran ◽  
Miroslava Kvandova ◽  
Amada D. Caliz ◽  
Hyung-Jin Yoo ◽  
...  
Keyword(s):  
Shear Stress ◽  
Reverse Transcriptase ◽  
Heme Oxygenase ◽  
Fluid Shear Stress ◽  
Heme Oxygenase 1 ◽  
Telomerase Reverse Transcriptase ◽  
Fluid Shear ◽  
Flow Alignment

Fluid shear stress (FSS) is known to mediate multiple phenotypic changes in the endothelium. Laminar FSS (undisturbed flow) is known to promote endothelial alignment to flow that is key to stabilizing the endothelium and rendering it resistant to atherosclerosis and thrombosis. The molecular pathways responsible for endothelial responses to FSS are only partially understood. Here we have identified peroxisome proliferator gamma coactivator-1α (PGC-1α) as a flow-responsive gene required for endothelial flow alignment in vitro and in vivo. Compared to oscillatory FSS (disturbed flow) or static conditions, laminar FSS (undisturbed flow) increased PGC-1α expression and its transcriptional co-activation. PGC-1α was required for laminar FSS-induced expression of telomerase reverse transcriptase (TERT) in vitro and in vivo via its association with ERRα and KLF4 on the TERT promoter. We found that TERT inhibition attenuated endothelial flow alignment, elongation, and nuclear polarization in response to laminar FSS in vitro and in vivo. Among the flow-responsive genes sensitive to TERT status was heme oxygenase-1 (HMOX1), a gene required for endothelial alignment to laminar FSS. Thus, these data suggest an important role for a PGC-1α-TERT-HMOX1 axis in the endothelial stabilization response to laminar FSS.

scholarly journals Role of HIF-1α-miR30a-Snai1 Axis in Neonatal Hyperoxic Lung Injury

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Yuhao Zhang ◽  
Xiaoyu Dong ◽  
Krithika Lingappan
Keyword(s):  
Lung Injury ◽  
Vascular Development ◽  
Female Mice ◽  
Severe Impairment ◽  
Hyperoxic Lung Injury ◽  
Postnatal Lung Development ◽  
Inhibitor Treatment

Bronchopulmonary dysplasia (BPD) is characterized by a severe impairment in lung alveolarization and vascular development. We have previously shown that pulmonary angiogenesis is preserved in hyperoxia-exposed female mice accompanied by increased miR-30a expression, which is a proangiogenic miRNA. Also, miR-30a expression is decreased in human BPD. HIF-1α plays an essential role in postnatal lung development, especially in recovery from hyperoxic injury. Snai1 activation promotes pathological fibrosis through many mechanisms including Endo-MT, which may in turn adversely impact lung vascular development. Our objective was to test the hypothesis that higher miR-30a expression through HIF-1α decreases Snai1 expression in females and attenuates injury in the developing lung. Neonatal male and female mice (C57BL/6) were exposed to hyperoxia (P1-5, 0.95 FiO2) and euthanized on P21. Neonatal human pulmonary microvascular endothelial cells (HPMECs; 18-24-week gestation donors; 3/group either sex) were subjected to hyperoxia (95% O2 and 5% CO2) or normoxia (air and 5% CO2) up to 72 h. Snai1 expression was measured in HPMECs in vitro and in neonatal mouse lungs in vivo. Also, Snai1 expression was measured in HPMECs after miR-30a mimic and miR-30a inhibitor treatment. To further establish the potential regulation of miR-30a by Hif-1α, miR-30a expression after Hif-1α inhibition was measured in HPMECs. In vivo, Snai1 expression was decreased in neonatal female lungs compared to males at P7. Increased Snai1 expression was seen in male HPMECs upon exposure to hyperoxia in vitro. Treatment with the miR-30a mimic decreased Snai1 expression in HPMECs, while miR-30a inhibition significantly increased Snai1 expression in HPMECs. siRNA-mediated loss of Hif-1α expression in HPMECs decreased miR-30a expression. Hif-1α may lead to differential sex-specific miR-30a expression and may contribute to protection from hyperoxic lung injury in female neonatal mice through decreased Snai1 expression.

scholarly journals Overexpression of Heme Oxygenase-1 in Mesenchymal Stem Cells Augments Their Protection on Retinal Cells In Vitro and Attenuates Retinal Ischemia/Reperfusion Injury In Vivo against Oxidative Stress

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Li Li ◽  
GaiPing Du ◽  
DaJiang Wang ◽  
Jin Zhou ◽  
Guomin Jiang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Heme Oxygenase ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Retinal Ischemia ◽  
Heme Oxygenase 1

Retinal ischemia/reperfusion (I/R) injury, involving several ocular diseases, seriously threatens human ocular health, mainly treated by attenuating I/R-induced oxidative stress. Currently, mesenchymal stem cells (MSCs) could restore I/R-injured retina through paracrine secretion. Additionally, heme oxygenase-1 (HO-1) could ameliorate oxidative stress and thus retinal apoptosis, but the expression of HO-1 in MSC is limited. Here, we hypothesized that overexpression of HO-1 in MSC (MSC-HO-1) may significantly improve their retina-protective potentials. The overexpression of HO-1 in MSC was achieved by lentivirus transduction. Then, MSC or MSC-HO-1 was cocultured with retinal ganglion cells (RGC-5) in H2O2-simulated oxidative condition and their protection on RGC-5 was systemically valuated in vitro. Compared with MSC, MSC-HO-1 significantly attenuated H2O2-induced injury of RGC-5, including decrease in cellular ROS level and apoptosis, activation of antiapoptotic proteins p-Akt and Bcl-2, and blockage of proapoptotic proteins cleaved caspase 3 and Bax. In retinal I/R rats model, compared with control MSC, MSC-HO-1-treated retina significantly retrieved its structural thickness, reduced cell apoptosis, markedly attenuated retinal oxidative stress level, and largely regained the activities of typical antioxidant enzymes, SOD and CAT. Therefore, it could be concluded that overexpression of HO-1 provides a promising strategy to enhance the MSC-based therapy for I/R-related retinal injury.

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