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New Insight into Heme Oxygenases: Beyond Heme Degradation

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Special Issue Information
Keywords
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A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 25057

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Special Issue Editors

Prof. Dr. Józef Dulak

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Guest Editor

Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Kraków, Poland
Interests: medical biotechnology; stem cells; gene therapy; inflammation; oxidative stress

Dr. Agnieszka Jaźwa-Kusior

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Guest Editor

Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Kraków, Poland
Interests: medical biotechnology; gene therapy; vascular remodeling; inflammation; oxidative stress

Dr. Agnieszka Łoboda

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Guest Editor

Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Kraków, Poland
Interests: heme oxygenase; vascular biology; medical biotechnology; inflammation; oxidative stress
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The significance of heme oxygenase (HO) system extends far beyond its primary role, which is heme degradation and antioxidant functions of HO by-products. Being among several enzymatic systems with constitutive and inducible isoforms, the HO-1 and HO-2 have in recent years been demonstrated to be involved in numerous biological processes. The different subcellular localisation, the non-enzymatic mechanism, the influence on such crucial processes like embryonic development, stem cell differentiation and function, non-coding and mRNA gene regulation are most probably not the only unexpected features of these intriguing proteins. The involvement of heme oxygenases and the related pathways: biliverdin reductase and ferritin in numerous physiological and pathological processes adds to the curiosity and complexity of the system, which we would like to elucidate by creating this special issue.

We would welcome the contribution of original and review articles. In this way, we invite you also to celebrate the 20th anniversary of the 1st meeting on heme oxygenases, held in New York in July 2000; and to go beyond the world pandemic which prevented many of us to take part in the 11th symposium scheduled for this June in Los Angeles.

Prof. Dr. Józef Dulak
Dr. Agnieszka Jaźwa-Kusior
Dr. Agnieszka Łoboda
Guest Editors

Manuscript Submission Information

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Keywords

Heme oxygenase-1
Heme oxygenase-2
Carbon monoxide
Biliverdin reductase
Inflammation
Gene expression
Stem cells

Published Papers (7 papers)

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Research

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14 pages, 2363 KiB

Open AccessCommunication

HO-1 and Heme: G-Quadruplex Interaction Choreograph DNA Damage Responses and Cancer Growth

by Giacomo Canesin, Anindhita Meena Muralidharan, Kenneth D. Swanson and Barbara Wegiel

Cells 2021, 10(7), 1801; https://doi.org/10.3390/cells10071801 - 16 Jul 2021

Cited by 12 | Viewed by 3382

Abstract

Many anti-cancer therapeutics lead to the release of danger associated pattern molecules (DAMPs) as the result of killing large numbers of both normal and transformed cells as well as lysis of red blood cells (RBC) (hemolysis). Labile heme originating from hemolysis acts as a DAMP while its breakdown products exert varying immunomodulatory effects. Labile heme is scavenged by hemopexin (Hx) and processed by heme oxygenase-1 (HO-1, Hmox1), resulting in its removal and the generation of biliverdin/bilirubin, carbon monoxide (CO) and iron. We recently demonstrated that labile heme accumulates in cancer cell nuclei in the tumor parenchyma of Hx knockout mice and contributes to the malignant phenotype of prostate cancer (PCa) cells and increased metastases. Additionally, this work identified Hx as a tumor suppressor gene. Direct interaction of heme with DNA G-quadruplexes (G4) leads to altered gene expression in cancer cells that regulate transcription, recombination and replication. Here, we provide new data supporting the nuclear role of HO-1 and heme in modulating DNA damage response, G4 stability and cancer growth. Finally, we discuss an alternative role of labile heme as a nuclear danger signal (NDS) that regulates gene expression and nuclear HO-1 regulated DNA damage responses stimulated by its interaction with G4. Full article

(This article belongs to the Special Issue New Insight into Heme Oxygenases: Beyond Heme Degradation)

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18 pages, 4167 KiB

Open AccessArticle

Heme Oxygenase-1 Contributes to Both the Engulfment and the Anti-Inflammatory Program of Macrophages during Efferocytosis

by Éva Fige, Judit Szendrei, László Sós, Izabela Kraszewska, László Potor, József Balla and Zsuzsa Szondy

Cells 2021, 10(3), 652; https://doi.org/10.3390/cells10030652 - 15 Mar 2021

Cited by 7 | Viewed by 2966

Abstract

Heme oxygenase-1 (HO-1) plays a vital role in the catabolism of heme and yields equimolar amounts of biliverdin, carbon monoxide, and free iron. We report that macrophages engulfing either the low amount of heme-containing apoptotic thymocytes or the high amount of heme-containing eryptotic red blood cells (eRBCs) strongly upregulate HO-1. The induction by apoptotic thymocytes is dependent on soluble signals, which do not include adenylate cyclase activators but induce the p38 mitogen-activated protein (MAP) kinase pathway, while in the case of eRBCs, it is cell uptake-dependent. Both pathways might involve the regulation of BTB and CNC homology 1 (BACH1), which is the repressor transcription regulator factor of the HO-1 gene. Long-term continuous efferocytosis of apoptotic thymocytes is not affected by the loss of HO-1, but that of eRBCs is inhibited. This latter is related to an internal signaling pathway that prevents the efferocytosis-induced increase in Rac1 activity. While the uptake of apoptotic cells suppressed the basal pro-inflammatory cytokine production in wild-type macrophages, in the absence of HO-1, engulfing macrophages produced enhanced amounts of pro-inflammatory cytokines. Our data demonstrate that HO-1 is required for both the engulfment and the anti-inflammatory response parts of the efferocytosis program. Full article

(This article belongs to the Special Issue New Insight into Heme Oxygenases: Beyond Heme Degradation)

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23 pages, 3462 KiB

Open AccessArticle

15-Deoxy-Δ^12,14-prostaglandin J₂ Upregulates VEGF Expression via NRF2 and Heme Oxygenase-1 in Human Breast Cancer Cells

by Eun-Hee Kim, Su-Jung Kim, Hye-Kyung Na, Wonshik Han, Nam-Jung Kim, Young-Ger Suh and Young-Joon Surh

Cells 2021, 10(3), 526; https://doi.org/10.3390/cells10030526 - 2 Mar 2021

Cited by 11 | Viewed by 2364

Abstract

There is a plethora of evidence to support that inflammation is causally linked to carcinogenesis. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme in the biosynthesis of prostaglandins, is inappropriately overexpressed in various cancers and hence recognized as one of the hallmarks of chronic inflammation-associated malignancies. However, the mechanistic role of COX-2 as a link between inflammation and cancer remains largely undefined. In this study, we found that 15-deoxy-Δ^12,14-prostaglandin J₂ (15d-PGJ₂), one of the final products of COX-2, induced upregulation of vascular endothelial growth factor (VEGF) and capillary formation and migration through nuclear factor erythroid 2-related factor 2 (NRF2)-dependent heme oxygenase-1 (HO-1) induction in MCF-7 cells. Analysis of the publicly available TCGA data set showed that high mRNA levels of both COX-2 and NRF2 correlated with the poor clinical outcomes in breast cancer patients. Moreover, human tissue analysis showed that the levels of 15d-PGJ₂ as well the expression of COX-2, NRF2, and HO-1 were found to be increased in human breast cancer tissues. In conclusion, the elevated levels of 15d-PGJ₂ during inflammatory response activate VEGF expression through NRF2-driven induction of HO-1 in human breast cancer cells, proposing a novel mechanism underlying the oncogenic function of 15d-PGJ₂. Full article

(This article belongs to the Special Issue New Insight into Heme Oxygenases: Beyond Heme Degradation)

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22 pages, 7315 KiB

Open AccessArticle

Role of Heme-Oxygenase-1 in Biology of Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells

by Mateusz Jeż, Alicja Martyniak, Kalina Andrysiak, Olga Mucha, Krzysztof Szade, Alan Kania, Łukasz Chrobok, Katarzyna Palus-Chramiec, Anna M. Sanetra, Marian H. Lewandowski, Ewelina Pośpiech, Jacek Stępniewski and Józef Dulak

Cells 2021, 10(3), 522; https://doi.org/10.3390/cells10030522 - 1 Mar 2021

Cited by 5 | Viewed by 2434

Abstract

Heme oxygenase-1 (HO-1, encoded by HMOX1) is a cytoprotective enzyme degrading heme into CO, Fe²⁺, and biliverdin. HO-1 was demonstrated to affect cardiac differentiation of murine pluripotent stem cells (PSCs), regulate the metabolism of murine adult cardiomyocytes, and influence regeneration of infarcted myocardium in mice. However, the enzyme’s effect on human cardiogenesis and human cardiomyocytes’ electromechanical properties has not been described so far. Thus, this study aimed to investigate the role of HO-1 in the differentiation of human induced pluripotent stem cells (hiPSCs) into hiPSC-derived cardiomyocytes (hiPSC-CMs). hiPSCs were generated from human fibroblasts and peripheral blood mononuclear cells using Sendai vectors and subjected to CRISPR/Cas9-mediated HMOX1 knock-out. After confirming lack of HO-1 expression on the protein level, isogenic control and HO-1-deficient hiPSCs were differentiated into hiPSC-CMs. No differences in differentiation efficiency and hiPSC-CMs metabolism were observed in both cell types. The global transcriptomic analysis revealed, on the other hand, alterations in electrophysiological pathways in hiPSC-CMs devoid of HO-1, which also demonstrated increased size. Functional consequences in changes in expression of ion channels genes were then confirmed by patch-clamp analysis. To the best of our knowledge, this is the first report demonstrating the link between HO-1 and electrophysiology in human cardiomyocytes. Full article

(This article belongs to the Special Issue New Insight into Heme Oxygenases: Beyond Heme Degradation)

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22 pages, 7143 KiB

Open AccessArticle

A Dual Role of Heme Oxygenase-1 in Angiotensin II-Induced Abdominal Aortic Aneurysm in the Normolipidemic Mice

by Aleksandra Kopacz, Damian Klóska, Ewa Werner, Karolina Hajduk, Anna Grochot-Przęczek, Alicja Józkowicz and Aleksandra Piechota-Polańczyk

Cells 2021, 10(1), 163; https://doi.org/10.3390/cells10010163 - 15 Jan 2021

Cited by 7 | Viewed by 2557

Abstract

Abdominal aortic aneurysm (AAA) bears a high risk of rupture and sudden death of the patient. The pathogenic mechanisms of AAA remain elusive, and surgical intervention represents the only treatment option. Heme oxygenase-1 (HO-1), a heme degrading enzyme, is induced in AAA, both in mice and humans. HO-1 was reported to mitigate AAA development in an angiotensin II (AngII)-induced model of AAA in hyperlipidemic ApoE^-/- mice. Since the role of hyperlipidaemia in the pathogenesis of AAA remains controversial, we aimed to evaluate the significance of HO-1 in the development and progression of AAA in normolipidemic animals. The experiments were performed in HO-1-deficient mice and their wild-type counterparts. We demonstrated in non-hypercholesterolemic mice that the high-dose of AngII leads to the efficient formation of AAA, which is attenuated by HO-1 deficiency. Yet, if formed, they are significantly more prone to rupture upon HO-1 shortage. Differential susceptibility to AAA formation does not rely on enhanced inflammatory response or oxidative stress. AAA-resistant mice are characterized by an increase in regulators of aortic remodeling and angiotensin receptor-2 expression, significant medial thickening, and delayed blood pressure elevation in response to AngII. To conclude, we unveil a dual role of HO-1 deficiency in AAA in normolipidemic mice, where it protects against AAA development, but exacerbates the state of formed AAA. Full article

(This article belongs to the Special Issue New Insight into Heme Oxygenases: Beyond Heme Degradation)

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17 pages, 2675 KiB

Open AccessArticle

Novel Interplay between p53 and HO-1 in Embryonic Stem Cells

by Ayelén Toro, Nicolás Anselmino, Claudia Solari, Marcos Francia, Camila Oses, Pablo Sanchis, Juan Bizzotto, Camila Vazquez Echegaray, María Victoria Petrone, Valeria Levi, Elba Vazquez and Alejandra Guberman

Cells 2021, 10(1), 35; https://doi.org/10.3390/cells10010035 - 29 Dec 2020

Cited by 8 | Viewed by 3508

Abstract

Stem cells genome safeguarding requires strict oxidative stress control. Heme oxygenase-1 (HO-1) and p53 are relevant components of the cellular defense system. p53 controls cellular response to multiple types of harmful stimulus, including oxidative stress. Otherwise, besides having a protective role, HO-1 is also involved in embryo development and in embryonic stem (ES) cells differentiation. Although both proteins have been extensively studied, little is known about their relationship in stem cells. The aim of this work is to explore HO-1-p53 interplay in ES cells. We studied HO-1 expression in p53 knockout (KO) ES cells and we found that they have higher HO-1 protein levels but similar HO-1 mRNA levels than the wild type (WT) ES cell line. Furthermore, cycloheximide treatment increased HO-1 abundance in p53 KO cells suggesting that p53 modulates HO-1 protein stability. Notably, H₂O₂ treatment did not induce HO-1 expression in p53 KO ES cells. Finally, SOD2 protein levels are also increased while Sod2 transcripts are not in KO cells, further suggesting that the p53 null phenotype is associated with a reinforcement of the antioxidant machinery. Our results demonstrate the existence of a connection between p53 and HO-1 in ES cells, highlighting the relationship between these stress defense pathways. Full article

(This article belongs to the Special Issue New Insight into Heme Oxygenases: Beyond Heme Degradation)

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Review

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25 pages, 1498 KiB

Open AccessReview

Heme Oxgenase-1, a Cardinal Modulator of Regulated Cell Death and Inflammation

by Stefan W. Ryter

Cells 2021, 10(3), 515; https://doi.org/10.3390/cells10030515 - 28 Feb 2021

Cited by 92 | Viewed by 7008

Abstract

Heme oxygenase catalyzes the rate-limiting step in heme degradation in order to generate biliverdin, carbon monoxide (CO), and iron. The inducible form of the enzyme, heme oxygenase-1 (HO-1), exerts a central role in cellular protection. The substrate, heme, is a potent pro-oxidant that can accelerate inflammatory injury and promote cell death. HO-1 has been implicated as a key mediator of inflammatory cell and tissue injury, as validated in preclinical models of acute lung injury and sepsis. A large body of work has also implicated HO-1 as a cytoprotective molecule against various forms of cell death, including necrosis, apoptosis and newly recognized regulated cell death (RCD) programs such as necroptosis, pyroptosis, and ferroptosis. While the antiapoptotic potential of HO-1 and its reaction product CO in apoptosis regulation has been extensively characterized, relatively fewer studies have explored the regulatory role of HO-1 in other forms of necrotic and inflammatory RCD (i.e., pyroptosis, necroptosis and ferroptosis). HO-1 may provide anti-inflammatory protection in necroptosis or pyroptosis. In contrast, in ferroptosis, HO-1 may play a pro-death role via enhancing iron release. HO-1 has also been implicated in co-regulation of autophagy, a cellular homeostatic program for catabolic recycling of proteins and organelles. While autophagy is primarily associated with cell survival, its occurrence can coincide with RCD programs. This review will summarize the roles of HO-1 and its reaction products in co-regulating RCD and autophagy programs, with its implication for both protective and detrimental tissue responses, with emphasis on how these impact HO-1 as a candidate therapeutic target in disease. Full article

(This article belongs to the Special Issue New Insight into Heme Oxygenases: Beyond Heme Degradation)

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