Role of Heme Oxygenase in Human Disease

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Antioxidant Enzyme Systems".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 22714

Special Issue Editor

Department of Pharmacy, Yasuda Women’s University, 6-13-1 Yasuhigashi, Asaminami-ku, Hiroshima 731-0153, Japan
Interests: oxidative stress; thermal stress; BACH1; NRF2; KEAP1; HSF1; MARE; HSE

Special Issue Information

Dear Colleagues,

Heme is essential for the maintenance of cellular homeostasis by sensing or using oxygen, however, an excess amount of free heme is deleterious, since it acts as a potent pro-oxidant, leading to the generation of reactive oxygen species (ROS). Physiological heme degradation is catalyzed by heme oxygenase (HO), which is a rate-limiting enzyme in heme catabolism, yielding CO, iron, and biliverdin IXα. Earlier studies have shown that expression of the inducible isoform of HO (HO-1) is increased in response to a large variety of environmental changes, including disease states, providing cytoprotective effects. One the other hand, several lines of evidence suggest that HO-1 may facilitate tumor growth, providing a basis for potential benefits through the targeting and reduction of HO-1 activity using specific inhibitors. The altered expression of HO is reportedly associated with pathophysiological conditions, such as disorders of the respiratory system, infectious diseases, neoplastic disorders, endocrine and metabolic disorders, disorders of the cardiovascular system, disorders of the gastrointestinal system, neurologic disorders, retinal diseases, and abnormal pregnancy. Induction or downregulation of HO expression in humans through pharmacological means will be a promising strategy for the treatment of various disorders.

This Special Issue aims to cover up-to-date information concerning the physiological role of HO, shedding light on the treatment of various disorders. Submissions on all aspects related HO are welcome.

Prof. Reiko Akagi
Guest Editor

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Keywords

  • heme oxygenase
  • heme
  • biliverdin/bilirubin
  • carbon monoxide
  • iron
  • stress response

Published Papers (6 papers)

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Research

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16 pages, 1940 KiB  
Article
BACH1 Expression Is Promoted by Tank Binding Kinase 1 (TBK1) in Pancreatic Cancer Cells to Increase Iron and Reduce the Expression of E-Cadherin
by Liang Liu, Mitsuyo Matsumoto, Miki Matsui-Watanabe, Kyoko Ochiai, Bert K. K. Callens, Long Chi Nguyen, Yushi Kozuki, Miho Tanaka, Hironari Nishizawa and Kazuhiko Igarashi
Antioxidants 2022, 11(8), 1460; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11081460 - 27 Jul 2022
Cited by 5 | Viewed by 2565
Abstract
BTB and CNC homology 1 (BACH1) represses the expression of genes involved in the metabolism of iron, heme and reactive oxygen species and promotes metastasis of various cancers including pancreatic ductal adenocarcinoma (PDAC). However, it is not clear how BACH1 is [...] Read more.
BTB and CNC homology 1 (BACH1) represses the expression of genes involved in the metabolism of iron, heme and reactive oxygen species and promotes metastasis of various cancers including pancreatic ductal adenocarcinoma (PDAC). However, it is not clear how BACH1 is regulated in PDAC cells. Knockdown of Tank binding kinase 1 (TBK1) led to reductions of BACH1 mRNA and protein amounts in AsPC−1 human PDAC cells. Gene expression analysis of PDAC cells with knockdown of TBK1 or BACH1 suggested the involvement of TBK1 and BACH1 in the regulation of iron homeostasis. Ferritin mRNA and proteins were both increased upon BACH1 knockdown in AsPC−1 cells. Flow cytometry analysis showed that AsPC−1 cells with BACH1 knockout or knockdown contained lower labile iron than control cells, suggesting that BACH1 increased labile iron by repressing the expression of ferritin genes. We further found that the expression of E-cadherin was upregulated upon the chelation of intracellular iron content. These results suggest that the TBK1-BACH1 pathway promotes cancer cell metastasis by increasing labile iron within cells. Full article
(This article belongs to the Special Issue Role of Heme Oxygenase in Human Disease)
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14 pages, 3355 KiB  
Article
Role and Potential Mechanism of Heme Oxygenase-1 in Intestinal Ischemia-Reperfusion Injury
by Kazuhiro Katada, Tomohisa Takagi, Takaya Iida, Tomohiro Ueda, Katsura Mizushima, Akifumi Fukui, Tetsuya Okayama, Kazuhiro Kamada, Kazuhiko Uchiyama, Takeshi Ishikawa, Yuji Naito and Yoshito Itoh
Antioxidants 2022, 11(3), 559; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11030559 - 15 Mar 2022
Cited by 2 | Viewed by 2123
Abstract
Intestinal ischemia-reperfusion (IR) injury is a complex, multifactorial, and pathophysiological condition with high morbidity and mortality, leading to serious difficulties in treatment, especially in humans. Heme oxygenase (HO) is the rate-limiting enzyme involved in heme catabolism. HO-1 (an inducible form) confers cytoprotection by [...] Read more.
Intestinal ischemia-reperfusion (IR) injury is a complex, multifactorial, and pathophysiological condition with high morbidity and mortality, leading to serious difficulties in treatment, especially in humans. Heme oxygenase (HO) is the rate-limiting enzyme involved in heme catabolism. HO-1 (an inducible form) confers cytoprotection by inhibiting inflammation and oxidation. Furthermore, nuclear factor-erythroid 2-related factor 2 (Nrf2) positively regulates HO-1 transcription, whereas BTB and CNC homolog 1 (Bach1) competes with Nrf2 and represses its transcription. We investigated the role and potential mechanism of action of HO-1 in intestinal IR injury. Intestinal ischemia was induced for 45 min followed by 4 h of reperfusion in wild-type, Bach1-deficient, and Nrf2-deficient mice, and a carbon monoxide (CO)-releasing molecule (CORM)-3 was administered. An increase in inflammatory marker levels, nuclear factor-κB (NF-κB) activation, and morphological impairments were observed in the IR-induced intestines of wild-type mice. These inflammatory changes were significantly attenuated in Bach1-deficient mice or those treated with CORM-3, and significantly exacerbated in Nrf2-deficient mice. Treatment with an HO-1 inhibitor reversed this attenuation in IR-induced Bach1-deficient mice. Bach1 deficiency and treatment with CORM-3 resulted in the downregulation of NF-κB activation and suppression of adhesion molecules. Together, Bach1, Nrf2, and CO are valuable therapeutic targets for intestinal IR injury. Full article
(This article belongs to the Special Issue Role of Heme Oxygenase in Human Disease)
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19 pages, 5969 KiB  
Article
HO-1 Modulates Aerobic Glycolysis through LDH in Prostate Cancer Cells
by Florencia Cascardo, Nicolás Anselmino, Alejandra Páez, Estefanía Labanca, Pablo Sanchis, Valeria Antico-Arciuch, Nora Navone, Geraldine Gueron, Elba Vázquez and Javier Cotignola
Antioxidants 2021, 10(6), 966; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10060966 - 16 Jun 2021
Cited by 10 | Viewed by 3531
Abstract
Prostate cancer (PCa) is the second most diagnosed malignancy and the fifth leading cause of cancer associated death in men worldwide. Dysregulation of cellular energetics has become a hallmark of cancer, evidenced by numerous connections between signaling pathways that include oncoproteins and key [...] Read more.
Prostate cancer (PCa) is the second most diagnosed malignancy and the fifth leading cause of cancer associated death in men worldwide. Dysregulation of cellular energetics has become a hallmark of cancer, evidenced by numerous connections between signaling pathways that include oncoproteins and key metabolic enzymes. We previously showed that heme oxygenase 1 (HO-1), a cellular homeostatic regulator counteracting oxidative and inflammatory damage, exhibits anti-tumoral activity in PCa cells, inhibiting cell proliferation, migration, tumor growth and angiogenesis. The aim of this study was to assess the role of HO-1 on the metabolic signature of PCa. After HO-1 pharmacological induction with hemin, PC3 and C4-2B cells exhibited a significantly impaired cellular metabolic rate, reflected by glucose uptake, ATP production, lactate dehydrogenase (LDH) activity and extracellular lactate levels. Further, we undertook a bioinformatics approach to assess the clinical significance of LDHA, LDHB and HMOX1 in PCa, identifying that high LDHA or low LDHB expression was associated with reduced relapse free survival (RFS). Interestingly, the shortest RFS was observed for PCa patients with low HMOX1 and high LDHA, while an improved prognosis was observed for those with high HMOX1 and LDHB. Thus, HO-1 induction causes a shift in the cellular metabolic profile of PCa, leading to a less aggressive phenotype of the disease. Full article
(This article belongs to the Special Issue Role of Heme Oxygenase in Human Disease)
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Review

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15 pages, 1039 KiB  
Review
Role of Heme Oxygenase in Gastrointestinal Epithelial Cells
by Reiko Akagi
Antioxidants 2022, 11(7), 1323; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11071323 - 05 Jul 2022
Cited by 8 | Viewed by 1720
Abstract
The gastrointestinal tract is a unique organ containing both vascular and luminal routes lined by epithelial cells forming the mucosa, which play an important role in the entry of nutrients and act as a selective barrier, excluding potentially harmful agents. Mucosal surfaces establish [...] Read more.
The gastrointestinal tract is a unique organ containing both vascular and luminal routes lined by epithelial cells forming the mucosa, which play an important role in the entry of nutrients and act as a selective barrier, excluding potentially harmful agents. Mucosal surfaces establish a selective barrier between hostile external environments and the internal milieu. Heme is a major nutritional source of iron and is a pro-oxidant that causes oxidative stress. Heme oxygenases (HOs) catalyze the rate-limiting step in heme degradation, resulting in the formation of iron, carbon monoxide, and biliverdin, which are subsequently converted to bilirubin by biliverdin reductase. In gastrointestinal pathogenesis, HO-1, an inducible isoform of HO, is markedly induced in epithelial cells and plays an important role in protecting mucosal cells. Recent studies have focused on the biological effects of the products of this enzymatic reaction, which have antioxidant, anti-inflammatory, and cytoprotective functions. In this review, the essential roles of HO in the gastrointestinal tract are summarized, focusing on nutrient absorption, protection against cellular stresses, and the maintenance and regulation of tight junction proteins, emphasizing the potential therapeutic implications. The biochemical basis of the potential therapeutic implications of glutamine for HO-1 induction in gastrointestinal injury is also discussed. Full article
(This article belongs to the Special Issue Role of Heme Oxygenase in Human Disease)
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26 pages, 1446 KiB  
Review
Heme Oxygenase-1: An Anti-Inflammatory Effector in Cardiovascular, Lung, and Related Metabolic Disorders
by Stefan W. Ryter
Antioxidants 2022, 11(3), 555; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11030555 - 15 Mar 2022
Cited by 68 | Viewed by 6926
Abstract
The heme oxygenase (HO) enzyme system catabolizes heme to carbon monoxide (CO), ferrous iron, and biliverdin-IXα (BV), which is reduced to bilirubin-IXα (BR) by biliverdin reductase (BVR). HO activity is represented by two distinct isozymes, the inducible form, HO-1, and a constitutive form, [...] Read more.
The heme oxygenase (HO) enzyme system catabolizes heme to carbon monoxide (CO), ferrous iron, and biliverdin-IXα (BV), which is reduced to bilirubin-IXα (BR) by biliverdin reductase (BVR). HO activity is represented by two distinct isozymes, the inducible form, HO-1, and a constitutive form, HO-2, encoded by distinct genes (HMOX1, HMOX2, respectively). HO-1 responds to transcriptional activation in response to a wide variety of chemical and physical stimuli, including its natural substrate heme, oxidants, and phytochemical antioxidants. The expression of HO-1 is regulated by NF-E2-related factor-2 and counter-regulated by Bach-1, in a heme-sensitive manner. Additionally, HMOX1 promoter polymorphisms have been associated with human disease. The induction of HO-1 can confer protection in inflammatory conditions through removal of heme, a pro-oxidant and potential catalyst of lipid peroxidation, whereas iron released from HO activity may trigger ferritin synthesis or ferroptosis. The production of heme-derived reaction products (i.e., BV, BR) may contribute to HO-dependent cytoprotection via antioxidant and immunomodulatory effects. Additionally, BVR and BR have newly recognized roles in lipid regulation. CO may alter mitochondrial function leading to modulation of downstream signaling pathways that culminate in anti-apoptotic, anti-inflammatory, anti-proliferative and immunomodulatory effects. This review will present evidence for beneficial effects of HO-1 and its reaction products in human diseases, including cardiovascular disease (CVD), metabolic conditions, including diabetes and obesity, as well as acute and chronic diseases of the liver, kidney, or lung. Strategies targeting the HO-1 pathway, including genetic or chemical modulation of HO-1 expression, or application of BR, CO gas, or CO donor compounds show therapeutic potential in inflammatory conditions, including organ ischemia/reperfusion injury. Evidence from human studies indicate that HO-1 expression may represent a biomarker of oxidative stress in various clinical conditions, while increases in serum BR levels have been correlated inversely to risk of CVD and metabolic disease. Ongoing human clinical trials investigate the potential of CO as a therapeutic in human disease. Full article
(This article belongs to the Special Issue Role of Heme Oxygenase in Human Disease)
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21 pages, 5221 KiB  
Review
Nrf2 and Heme Oxygenase-1 Involvement in Atherosclerosis Related Oxidative Stress
by Jose Angel Alonso-Piñeiro, Almudena Gonzalez-Rovira, Ismael Sánchez-Gomar, Juan Antonio Moreno and Ma Carmen Durán-Ruiz
Antioxidants 2021, 10(9), 1463; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10091463 - 14 Sep 2021
Cited by 49 | Viewed by 4722
Abstract
Atherosclerosis remains the underlying process responsible for cardiovascular diseases and the high mortality rates associated. This chronic inflammatory disease progresses with the formation of occlusive atherosclerotic plaques over the inner walls of vascular vessels, with oxidative stress being an important element of this [...] Read more.
Atherosclerosis remains the underlying process responsible for cardiovascular diseases and the high mortality rates associated. This chronic inflammatory disease progresses with the formation of occlusive atherosclerotic plaques over the inner walls of vascular vessels, with oxidative stress being an important element of this pathology. Oxidation of low-density lipoproteins (ox-LDL) induces endothelial dysfunction, foam cell activation, and inflammatory response, resulting in the formation of fatty streaks in the atherosclerotic wall. With this in mind, different approaches aim to reduce oxidative damage as a strategy to tackle the progression of atherosclerosis. Special attention has been paid in recent years to the transcription factor Nrf2 and its downstream-regulated protein heme oxygenase-1 (HO-1), both known to provide protection against atherosclerotic injury. In the current review, we summarize the involvement of oxidative stress in atherosclerosis, focusing on the role that these antioxidant molecules exert, as well as the potential therapeutic strategies applied to enhance their antioxidant and antiatherogenic properties. Full article
(This article belongs to the Special Issue Role of Heme Oxygenase in Human Disease)
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