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Kipp ZA, Badmus OO, Stec DE, Hall B, Hinds TD. Bilirubin bioconversion to urobilin in the gut-liver-kidney axis: A biomarker for insulin resistance in the Cardiovascular-Kidney-Metabolic (CKM) Syndrome. Metabolism 2025; 163:156081. [PMID: 39580049 DOI: 10.1016/j.metabol.2024.156081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 10/17/2024] [Accepted: 11/16/2024] [Indexed: 11/25/2024]
Abstract
The rising rates of obesity worldwide have increased the incidence of cardiovascular disease (CVD), making it the number one cause of death. Higher plasma bilirubin levels have been shown to prevent metabolic dysfunction and CVD. However, reducing levels leads to deleterious outcomes, possibly due to reduced bilirubin half-life that escalates the production of its catabolized product, urobilinogen, produced by gut bacteria and naturally oxidized to urobilin. Recent findings suggest that the involvement of the microbiome catabolism of bilirubin to urobilin and its absorption via the hepatic portal vein contributes to CVD, suggesting a liver-gut axis involvement. We discuss the studies that demonstrate that urobilin is frequently raised in the urine of persons with CVD and its probable role in acquiring the disease. Urobilin is excreted from the kidneys into the urine and may serve as a biomarker for Cardiovascular-Kidney-Metabolic (CKM) Syndrome. We deliberate on the newly discovered bilirubin reductase (BilR) bacterial enzyme that produces urobilin. We discuss the bacterial species expressing BilR, how they impact CVD, and whether suppressing urobilin production and increasing bilirubin may provide new therapeutic strategies for CKM. Possible therapeutic mechanisms for achieving this goal are discussed.
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Affiliation(s)
- Zachary A Kipp
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Olufunto O Badmus
- Department of Physiology and Biophysics, Cardiorenal, and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS, USA
| | - David E Stec
- Department of Physiology and Biophysics, Cardiorenal, and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS, USA
| | - Brantley Hall
- Center for Bioinformatics and Computational Biology, Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, College Park, MD, USA
| | - Terry D Hinds
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA.
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Wang E, Hao Y, Song J, Yuan J, Hong Y, Li Y, Wang Y, Wang C, Wang M, Zhang L. M2 macrophage derived HMOX1 defines chronic rhinosinusitis with nasal polyps. Clin Transl Allergy 2024; 14:e70014. [PMID: 39644500 PMCID: PMC11624889 DOI: 10.1002/clt2.70014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 10/23/2024] [Accepted: 11/24/2024] [Indexed: 12/09/2024] Open
Abstract
BACKGROUND Molecular signatures of chronic rhinosinusitis with nasal polyps (CRSwNP) related to macrophages remain unclear. This study aimed to develop a macrophage-associated diagnostic signature for CRSwNP. METHODS Transcriptome data from 54 patients with CRSwNP and 37 healthy controls across GSE136825, GSE36830, and GSE72713 were used to identify differentially expressed genes (DEGs) between two groups. Gene Set Enrichment Analysis and Weighted Gene Co-Expression Network Analysis pinpointed crucial pathways and gene clusters. A diagnostic model was created from these analyses and receiver operating characteristic curve (ROC), and further validated in our transcriptome data from 29 samples. Immune cell infiltration analysis was performed and linked those diagnostic genes to macrophages and verified by single-cell RNA sequencing data. Immunofluorescence co-staining of CD163 and HMOX1 was performed in nasal tissues. Mouse bone marrow-derived macrophage (BMDMs) cultures were used in functional experiments. Correlations between the expression of HMOX1 and eotaxin genes were investigated. RESULTS DEGs of CRSwNP versus control group were enriched in the INTERLEUKIN_4_AND_13_SIGNALING pathways. A four-gene diagnostic model (HMOX1, ALOX5, F13A1 and ITGB2) was developed and demonstrated high diagnostic precision with an area under ROC curve of 0.980 for training dataset and 0.895 for test dataset. M2 macrophage presence and HMOX1 expression significantly correlated with CRSwNP (p < 0.001). Single-cell RNA sequencing data underscored the altered cellular composition in CRSwNP, with HMOX1 notably expressed in M2 macrophages. Immunofluorescence staining highlighted the increased infiltration of CD163+ M2 macrophages in nasal mucosa samples of eosinophilic CRSwNP, which correlated with HMOX1 protein levels (p < 0.05). The HMOX1 inhibitor zinc protoporphyrin reduced the ratio of CD163 + HMOX1 + M2 macrophages in mouse BMDM cultures (p < 0.05). HMOX1 expression showed a strong positive correlation with the expression of eotaxin genes (CCL11, CCL24, and CCL26; p < 0.05 respectively). CONCLUSION M2 macrophage-derived HMOX1 can be used as an innovative diagnostic signature for CRSwNP, which might be a potential regulator of eosinophilic inflammation.
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Affiliation(s)
- Enhao Wang
- Department of OtolaryngologyHead and Neck SurgeryBeijing TongRen HospitalCapital Medical UniversityBeijingChina
- Beijing Institute of OtolaryngologyBeijing Laboratory of Allergic DiseasesBeijing Key Laboratory of Nasal DiseasesKey Laboratory of Otolaryngology Head and Neck SurgeryMinistry of EducationCapital Medical UniversityBeijingChina
- Research Unit of Diagnosis and Treatment of Chronic Nasal DiseasesChinese Academy of Medical SciencesBeijingChina
| | - Yanghe Hao
- Department of OtolaryngologyHead and Neck SurgeryBeijing TongRen HospitalCapital Medical UniversityBeijingChina
- Beijing Institute of OtolaryngologyBeijing Laboratory of Allergic DiseasesBeijing Key Laboratory of Nasal DiseasesKey Laboratory of Otolaryngology Head and Neck SurgeryMinistry of EducationCapital Medical UniversityBeijingChina
- Research Unit of Diagnosis and Treatment of Chronic Nasal DiseasesChinese Academy of Medical SciencesBeijingChina
| | - Jing Song
- Department of OtolaryngologyHead and Neck SurgeryBeijing TongRen HospitalCapital Medical UniversityBeijingChina
- Beijing Institute of OtolaryngologyBeijing Laboratory of Allergic DiseasesBeijing Key Laboratory of Nasal DiseasesKey Laboratory of Otolaryngology Head and Neck SurgeryMinistry of EducationCapital Medical UniversityBeijingChina
- Research Unit of Diagnosis and Treatment of Chronic Nasal DiseasesChinese Academy of Medical SciencesBeijingChina
| | - Jing Yuan
- Department of OtolaryngologyHead and Neck SurgeryBeijing TongRen HospitalCapital Medical UniversityBeijingChina
- Beijing Institute of OtolaryngologyBeijing Laboratory of Allergic DiseasesBeijing Key Laboratory of Nasal DiseasesKey Laboratory of Otolaryngology Head and Neck SurgeryMinistry of EducationCapital Medical UniversityBeijingChina
- Research Unit of Diagnosis and Treatment of Chronic Nasal DiseasesChinese Academy of Medical SciencesBeijingChina
| | - Yu Hong
- Department of OtolaryngologyHead and Neck SurgeryBeijing TongRen HospitalCapital Medical UniversityBeijingChina
- Beijing Institute of OtolaryngologyBeijing Laboratory of Allergic DiseasesBeijing Key Laboratory of Nasal DiseasesKey Laboratory of Otolaryngology Head and Neck SurgeryMinistry of EducationCapital Medical UniversityBeijingChina
- Research Unit of Diagnosis and Treatment of Chronic Nasal DiseasesChinese Academy of Medical SciencesBeijingChina
| | - Ying Li
- Department of OtolaryngologyHead and Neck SurgeryBeijing TongRen HospitalCapital Medical UniversityBeijingChina
- Beijing Institute of OtolaryngologyBeijing Laboratory of Allergic DiseasesBeijing Key Laboratory of Nasal DiseasesKey Laboratory of Otolaryngology Head and Neck SurgeryMinistry of EducationCapital Medical UniversityBeijingChina
- Research Unit of Diagnosis and Treatment of Chronic Nasal DiseasesChinese Academy of Medical SciencesBeijingChina
| | - Yang Wang
- Department of OtolaryngologyHead and Neck SurgeryBeijing TongRen HospitalCapital Medical UniversityBeijingChina
- Beijing Institute of OtolaryngologyBeijing Laboratory of Allergic DiseasesBeijing Key Laboratory of Nasal DiseasesKey Laboratory of Otolaryngology Head and Neck SurgeryMinistry of EducationCapital Medical UniversityBeijingChina
- Research Unit of Diagnosis and Treatment of Chronic Nasal DiseasesChinese Academy of Medical SciencesBeijingChina
| | - Chengshuo Wang
- Department of OtolaryngologyHead and Neck SurgeryBeijing TongRen HospitalCapital Medical UniversityBeijingChina
- Beijing Institute of OtolaryngologyBeijing Laboratory of Allergic DiseasesBeijing Key Laboratory of Nasal DiseasesKey Laboratory of Otolaryngology Head and Neck SurgeryMinistry of EducationCapital Medical UniversityBeijingChina
- Research Unit of Diagnosis and Treatment of Chronic Nasal DiseasesChinese Academy of Medical SciencesBeijingChina
| | - Ming Wang
- Department of OtolaryngologyHead and Neck SurgeryBeijing TongRen HospitalCapital Medical UniversityBeijingChina
- Beijing Institute of OtolaryngologyBeijing Laboratory of Allergic DiseasesBeijing Key Laboratory of Nasal DiseasesKey Laboratory of Otolaryngology Head and Neck SurgeryMinistry of EducationCapital Medical UniversityBeijingChina
- Research Unit of Diagnosis and Treatment of Chronic Nasal DiseasesChinese Academy of Medical SciencesBeijingChina
| | - Luo Zhang
- Department of OtolaryngologyHead and Neck SurgeryBeijing TongRen HospitalCapital Medical UniversityBeijingChina
- Beijing Institute of OtolaryngologyBeijing Laboratory of Allergic DiseasesBeijing Key Laboratory of Nasal DiseasesKey Laboratory of Otolaryngology Head and Neck SurgeryMinistry of EducationCapital Medical UniversityBeijingChina
- Research Unit of Diagnosis and Treatment of Chronic Nasal DiseasesChinese Academy of Medical SciencesBeijingChina
- Department of AllergyBeijing TongRen HospitalCapital Medical UniversityBeijingChina
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Bilska B, Damulewicz M, Abaquita TAL, Pyza E. Changes in heme oxygenase level during development affect the adult life of Drosophila melanogaster. Front Cell Neurosci 2023; 17:1239101. [PMID: 37876913 PMCID: PMC10591093 DOI: 10.3389/fncel.2023.1239101] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 09/15/2023] [Indexed: 10/26/2023] Open
Abstract
Heme oxygenase (HO) has been shown to control various cellular processes in both mammals and Drosophila melanogaster. Here, we investigated how changes in HO levels in neurons and glial cells during development affect adult flies, by using the TARGET Drosophila system to manipulate the expression of the ho gene. The obtained data showed differences in adult survival, maximum lifespan, climbing, locomotor activity, and sleep, which depended on the level of HO (after ho up-regulation or downregulation), the timing of expression (chronic or at specific developmental stages), cell types (neurons or glia), sex (males or females), and age of flies. In addition to ho, the effects of changing the mRNA level of the Drosophila CNC factor gene (NRF2 homolog in mammals and master regulator of HO), were also examined to compare with those observed after changing ho expression. We showed that HO levels in neurons and glia must be maintained at an appropriate physiological level during development to ensure the well-being of adults. We also found that the downregulation of ho in either neurons or glia in the brain is compensated by ho expressed in the retina.
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Affiliation(s)
| | | | | | - Elzbieta Pyza
- Department of Cell Biology and Imaging, Institute of Zoology and Biomedical Research, Jagiellonian University, Cracow, Poland
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Mancuso C. The impact of heme oxygenase-2 on pharmacological research: A bibliometric analysis and beyond. Front Pharmacol 2023; 14:1156333. [PMID: 37153762 PMCID: PMC10154548 DOI: 10.3389/fphar.2023.1156333] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 04/06/2023] [Indexed: 05/10/2023] Open
Abstract
Heme oxygenase (HO-2) is an enzyme mainly involved in the physiologic turnover of heme and intracellular gas sensing, and it is very abundant in the brain, testes, kidneys and vessels. Since 1990, when HO-2 was discovered, the scientific community has underestimated the role of this protein in health and disease, as attested by the small amount of articles published and citations received. One of the reason that have contributed to the lack of interest in HO-2 was the difficulty in upregulating or inhibiting this enzyme. However, over the last 10 years, novel HO-2 agonists and antagonists have been synthesized, and the availability of these pharmacological tools should increase the appeal of HO-2 as drug target. In particular, these agonists and antagonists could help explain some controversial aspects, such as the neuroprotective versus neurotoxic roles of HO-2 in cerebrovascular diseases. Furthermore, the discovery of HO-2 genetic variants and their involvement in Parkinson's disease, in particular in males, opens new avenues for pharmacogenetic studies in gender medicine.
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Affiliation(s)
- Cesare Mancuso
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Department of Healthcare Surveillance and Bioethics, Section of Pharmacology, Università Cattolica Del Sacro Cuore, Rome, Italy
- *Correspondence: Cesare Mancuso,
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Abstract
How oxygen is sensed by the heart and what mechanisms mediate its sensing remain poorly understood. Since recent reports show that low PO2 levels are detected by the cardiomyocytes in a few seconds, the rapid and short applications of low levels of oxygen (acute hypoxia), that avoid multiple effects of chronic hypoxia may be used to probe the oxygen sensing pathway of the heart. Here we explore the oxygen sensing pathway, focusing primarily on cellular surface membrane proteins that are first exposed to low PO2. Such studies suggest that acute hypoxia primarily targets the cardiac calcium channels, where either the channel itself or moieties closely associated with it, for instance, heme-oxygenase-2 (HO-2) interacting through kinase phosphorylation, signals the α-subunit of the channel as to the altered levels of PO2. Amino acids 1572-1651, the CaMKII phosphorylation sites (S1487 and S1545), CaM-binding site (I1624, Q1625) and Ser1928 of the carboxyl tail of the α-subunit appear to be critical residues that sense oxygen. Future studies in HO-2 knockout mice or CRISPR/Cas9 gene-edited hiPSC-CMs that reduce CaM-binding affinity are likely to provide deeper insights in the O2-sensinsing mechanisms.
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Affiliation(s)
| | - Martin Morad
- USC, MUSC, and Clemson University, Cardiac Signaling Center, Charleston, South Carolina, United States;
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Magierowska K, Magierowski M. COin Gastrointestinal Physiology and Protection. CARBON MONOXIDE IN DRUG DISCOVERY 2022:466-481. [DOI: 10.1002/9781119783435.ch27] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Lu Z, Tang M, Zhang M, Li Y, Shi F, Zhan F, Zhao L, Li J, Lin L, Qin Z. Hemeprotein amplifies the innate immune receptors of Ctenopharyngodon idellus kidney cells through NF-κB- and MAPK-dependent reactive oxygen species generation. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2022; 126:104207. [PMID: 34273355 DOI: 10.1016/j.dci.2021.104207] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 07/13/2021] [Accepted: 07/14/2021] [Indexed: 06/13/2023]
Abstract
Infectious bacterial and viral diseases that cause hemolysis are considered life-threatening to grass carp (Ctenopharyngodon idellus), which is a species used in aquaculture worldwide. After heme and hemeproteins (Hb) are released as a result of hemolysis, the effect of excess Hb and heme on tissues remains to be characterized. To decipher the mechanisms, after incubation with Hb, we showed that lipopolysaccharide (LPS), Hb, and heme increased the cytotoxicity and secretion of inflammatory cytokines such as interleukin (IL)-6, chemokine (C-C motif) ligand 1 (CCL1), tumor necrosis factor (TNF)-α, IL-6, and IL-1β in vitro, which was due to stimulation of the expression of innate immune receptors, such as nucleotide-binding oligomerization domain (NOD2), toll-like receptor 2 (TLR2), TLR 4, and TLR3. The formation of reactive oxygen species (ROS) and the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-κB were important for increasing the cytokine production to induce heme, Hb, and LPS. Moreover, we confirmed that after LPS, Hb, and heme challenge, superoxide dismutase (SOD) and glutathione (GSH) synthetase (GSS) also caused remarkable destruction. However, catalase (CAT) and heme oxygenase-1 (HO-1) were strongly activated. In summary, our research findings present a framework through which heme and Hb concentrations amplify the secretions of inflammatory cytokines, which are induced by pattern recognition receptor (PRR) activation and present possible paths for immune intervention during infection with viral diseases and hemolytic bacterial.
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Affiliation(s)
- Zhijie Lu
- Guangdong Provincial Water Environment and Aquatic Products Security Engineering Technology Research Center, Guangzhou Key Laboratory of Aquatic Animal Diseases and Waterfowl Breeding, College of Animal Sciences and Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, Guangdong Province, 510222, China
| | - Meizhen Tang
- Guangdong Provincial Water Environment and Aquatic Products Security Engineering Technology Research Center, Guangzhou Key Laboratory of Aquatic Animal Diseases and Waterfowl Breeding, College of Animal Sciences and Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, Guangdong Province, 510222, China
| | - Menglan Zhang
- Guangdong Provincial Water Environment and Aquatic Products Security Engineering Technology Research Center, Guangzhou Key Laboratory of Aquatic Animal Diseases and Waterfowl Breeding, College of Animal Sciences and Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, Guangdong Province, 510222, China
| | - Yanan Li
- Guangdong Provincial Water Environment and Aquatic Products Security Engineering Technology Research Center, Guangzhou Key Laboratory of Aquatic Animal Diseases and Waterfowl Breeding, College of Animal Sciences and Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, Guangdong Province, 510222, China
| | - Fei Shi
- Guangdong Provincial Water Environment and Aquatic Products Security Engineering Technology Research Center, Guangzhou Key Laboratory of Aquatic Animal Diseases and Waterfowl Breeding, College of Animal Sciences and Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, Guangdong Province, 510222, China
| | - Fanbin Zhan
- Guangdong Provincial Water Environment and Aquatic Products Security Engineering Technology Research Center, Guangzhou Key Laboratory of Aquatic Animal Diseases and Waterfowl Breeding, College of Animal Sciences and Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, Guangdong Province, 510222, China
| | - Lijuan Zhao
- Guangdong Provincial Water Environment and Aquatic Products Security Engineering Technology Research Center, Guangzhou Key Laboratory of Aquatic Animal Diseases and Waterfowl Breeding, College of Animal Sciences and Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, Guangdong Province, 510222, China
| | - Jun Li
- Guangdong Provincial Water Environment and Aquatic Products Security Engineering Technology Research Center, Guangzhou Key Laboratory of Aquatic Animal Diseases and Waterfowl Breeding, College of Animal Sciences and Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, Guangdong Province, 510222, China; School of Biological Sciences, Lake Superior State University, Sault Ste. Marie, MI, 49783, USA
| | - Li Lin
- Guangdong Provincial Water Environment and Aquatic Products Security Engineering Technology Research Center, Guangzhou Key Laboratory of Aquatic Animal Diseases and Waterfowl Breeding, College of Animal Sciences and Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, Guangdong Province, 510222, China.
| | - Zhendong Qin
- Guangdong Provincial Water Environment and Aquatic Products Security Engineering Technology Research Center, Guangzhou Key Laboratory of Aquatic Animal Diseases and Waterfowl Breeding, College of Animal Sciences and Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, Guangdong Province, 510222, China.
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Park J, Zeng JS, Sahasrabudhe A, Jin K, Fink Y, Manthiram K, Anikeeva P. Electrochemical Modulation of Carbon Monoxide‐Mediated Cell Signaling. Angew Chem Int Ed Engl 2021. [DOI: 10.1002/ange.202103228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Jimin Park
- Department of Materials Science and Engineering Massachusetts Institute of Technology Cambridge MA 02139 USA
- Research Laboratory of Electronics and McGovern Institute for Brain Research Massachusetts Institute of Technology Cambridge MA 02139 USA
| | - Joy S. Zeng
- Department of Chemical Engineering Massachusetts Institute of Technology Cambridge MA 02139 USA
| | - Atharva Sahasrabudhe
- Research Laboratory of Electronics and McGovern Institute for Brain Research Massachusetts Institute of Technology Cambridge MA 02139 USA
- Department of Chemistry Massachusetts Institute of Technology Cambridge MA 02139 USA
| | - Kyoungsuk Jin
- Department of Chemical Engineering Massachusetts Institute of Technology Cambridge MA 02139 USA
| | - Yoel Fink
- Department of Materials Science and Engineering Massachusetts Institute of Technology Cambridge MA 02139 USA
| | - Karthish Manthiram
- Department of Chemical Engineering Massachusetts Institute of Technology Cambridge MA 02139 USA
| | - Polina Anikeeva
- Department of Materials Science and Engineering Massachusetts Institute of Technology Cambridge MA 02139 USA
- Research Laboratory of Electronics and McGovern Institute for Brain Research Massachusetts Institute of Technology Cambridge MA 02139 USA
- Department of Brain and Cognitive Sciences Massachusetts Institute of Technology Cambridge MA 02139 USA
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Park J, Zeng JS, Sahasrabudhe A, Jin K, Fink Y, Manthiram K, Anikeeva P. Electrochemical Modulation of Carbon Monoxide-Mediated Cell Signaling. Angew Chem Int Ed Engl 2021; 60:20325-20330. [PMID: 34265141 PMCID: PMC8405587 DOI: 10.1002/anie.202103228] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Indexed: 11/08/2022]
Abstract
Despite the critical role played by carbon monoxide (CO) in physiological and pathological signaling events, current approaches to deliver this messenger molecule are often accompanied by off-target effects and offer limited control over release kinetics. To address these challenges, we develop an electrochemical approach that affords on-demand release of CO through reduction of carbon dioxide (CO2 ) dissolved in the extracellular space. Electrocatalytic generation of CO by cobalt phthalocyanine molecular catalysts modulates signaling pathways mediated by a CO receptor soluble guanylyl cyclase. Furthermore, by tuning the applied voltage during electrocatalysis, we explore the effect of the CO release kinetics on CO-dependent neuronal signaling. Finally, we integrate components of our electrochemical platform into microscale fibers to produce CO in a spatially-restricted manner and to activate signaling cascades in the targeted cells. By offering on-demand local synthesis of CO, our approach may facilitate the studies of physiological processes affected by this gaseous molecular messenger.
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Affiliation(s)
- Jimin Park
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
- Research Laboratory of Electronics and McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Joy S Zeng
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Atharva Sahasrabudhe
- Research Laboratory of Electronics and McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Kyoungsuk Jin
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Yoel Fink
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Karthish Manthiram
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Polina Anikeeva
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
- Research Laboratory of Electronics and McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
- Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
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Sharma A, Muresanu DF, Castellani RJ, Nozari A, Lafuente JV, Sahib S, Tian ZR, Buzoianu AD, Patnaik R, Wiklund L, Sharma HS. Mild traumatic brain injury exacerbates Parkinson's disease induced hemeoxygenase-2 expression and brain pathology: Neuroprotective effects of co-administration of TiO 2 nanowired mesenchymal stem cells and cerebrolysin. PROGRESS IN BRAIN RESEARCH 2020; 258:157-231. [PMID: 33223035 DOI: 10.1016/bs.pbr.2020.09.010] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Mild traumatic brain injury (mTBI) is one of the leading predisposing factors in the development of Parkinson's disease (PD). Mild or moderate TBI induces rapid production of tau protein and alpha synuclein (ASNC) in the cerebrospinal fluid (CSF) and in several brain areas. Enhanced tau-phosphorylation and ASNC alters the molecular machinery of the brain leading to PD pathology. Recent evidences show upregulation of constitutive isoform of hemeoxygenase (HO-2) in PD patients that correlates well with the brain pathology. mTBI alone induces profound upregulation of HO-2 immunoreactivity. Thus, it would be interesting to explore whether mTBI exacerbates PD pathology in relation to tau, ASNC and HO-2 expression. In addition, whether neurotrophic factors and stem cells known to reduce brain pathology in TBI could induce neuroprotection in PD following mTBI. In this review role of mesenchymal stem cells (MSCs) and cerebrolysin (CBL), a well-balanced composition of several neurotrophic factors and active peptide fragments using nanowired delivery in PD following mTBI is discussed based on our own investigation. Our results show that mTBI induces concussion exacerbates PD pathology and nanowired delivery of MSCs and CBL induces superior neuroprotection. This could be due to reduction in tau, ASNC and HO-2 expression in PD following mTBI, not reported earlier. The functional significance of our findings in relation to clinical strategies is discussed.
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Affiliation(s)
- Aruna Sharma
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.
| | - Dafin F Muresanu
- Department of Clinical Neurosciences, University of Medicine & Pharmacy, Cluj-Napoca, Romania; "RoNeuro" Institute for Neurological Research and Diagnostic, Cluj-Napoca, Romania
| | - Rudy J Castellani
- Department of Pathology, University of Maryland, Baltimore, MD, United States
| | - Ala Nozari
- Anesthesiology & Intensive Care, Massachusetts General Hospital, Boston, MA, United States
| | - José Vicente Lafuente
- LaNCE, Department of Neuroscience, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain
| | - Seaab Sahib
- Department of Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, United States
| | - Z Ryan Tian
- Department of Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, United States
| | - Anca D Buzoianu
- Department of Clinical Pharmacology and Toxicology, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Ranjana Patnaik
- Department of Biomaterials, School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi, India
| | - Lars Wiklund
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden
| | - Hari Shanker Sharma
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.
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11
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Kadinov B, Itzev D. Influence between NO and CO in guinea pig stomach fundus. PHARMACIA 2020. [DOI: 10.3897/pharmacia.67.e52474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The interaction between carbon monoxide and nitric oxide and their role in modulation of stomach fundus excitability was studied. The presence and colocalization of heme oxygenase 1 (HO-1) and nitric oxide synthase (NOS) was verified in myentheric ganglia by immunohistochemistry. The role of inducible heme oxygenase isoenzyme was investigated after in vivo treatment of animals with CoCl2 (80 mg kg-1 b.w.) injected subcutaneously 24 hours before euthanasia. This treatment resulted in positive staining for the inducible isoform in stomach smooth muscle.
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Heme Oxygenase-2 (HO-2) as a therapeutic target: Activators and inhibitors. Eur J Med Chem 2019; 183:111703. [PMID: 31550661 DOI: 10.1016/j.ejmech.2019.111703] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 09/13/2019] [Accepted: 09/14/2019] [Indexed: 12/24/2022]
Abstract
Heme oxygenase (HO) enzymes are involved in heme catabolism and several physiological functions. Among the different HO isoforms, HO-2 stands out for its neuroprotective properties and modulatory activity in male reproduction. However, unlike the HO-1 ligands, the potential therapeutic applications of HO-2 inhibitors/activators have not been extensively explored yet. Moreover, the physiological role of HO-2 is still unclear, mostly due to the lack of highly selective HO-2 chemical probes. To boost the interest on this intriguing target, the present review updates the knowledge on the structure-activity relationships of HO-2 inhibitors and activators, as well as their potential therapeutic applications. To the best of our knowledge, among HO-2 inhibitors, clemizole derivatives are the most selective HO-2 inhibitors reported so far (IC50 HO-1 >100 μM, IC50 HO-2 = 3.4 μM), while the HO-2 nonselective inhibitors described herein possess IC50 HO-2 values ≤ 10 μM. Furthermore, the development of HO-2 activators, such as menadione analogues, helped to understand the critical moieties required for HO-2 activation. Recent advances in the potential therapeutic applications of HO-2 inhibitors/activators cover the fields of neurodegenerative, cardiovascular, inflammatory, and reproductive diseases further stimulating the interest towards this target.
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Liu C, Zhu P, Fujino M, Zhu S, Ito H, Takahashi K, Nakajima M, Tanaka T, Zhuang J, Li XK. 5-ALA/SFC Attenuated Binge Alcohol-Induced Gut Leakiness and Inflammatory Liver Disease in HIV Transgenic Rats. Alcohol Clin Exp Res 2019; 43:1651-1661. [PMID: 31141180 DOI: 10.1111/acer.14117] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Accepted: 05/14/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND This study aimed to investigate the protective effect of 5-aminolevulinic acid (5-ALA) and sodium ferrous citrate (SFC) against binge alcohol-induced gut leakiness and inflammatory liver disease in HIV transgenic (TG) rats. METHODS TG rats were treated with 3 consecutive doses of binge ethanol (EtOH) with or without 5-ALA/SFC. Blood and liver tissue samples were collected at 6 hours following the last dose of EtOH. RESULTS Compared with the wild-type (WT) rats, the TG rats showed increased sensitivity to alcohol-mediated inflammation, as evidenced by the significantly elevated levels of serum endotoxin, AST, ALT, ED1, and ED2 staining in liver. In contrast, 5-ALA/SFC improved the above biochemical and histochemical profiles. 5-ALA/SFC also attenuated the up-regulated mRNA expression of leptin and CCL2. Furthermore, down-regulated intestinal ZO-1 protein expression was also inhibited by 5-ALA/SFC. Moreover, the expressions of HO-1, HO-2, Sirt1, and related signal transduction molecules in liver were increased by 5-ALA/SFC. These results demonstrated that 5-ALA/SFC treatment ameliorated binge alcohol exposure liver injury in a rat model of HIV-infected patients by reducing macrophage activation and expression of inflammatory cytokines/chemokines, and by inducing HO-1, HO-2, and Sirt1 expression. CONCLUSIONS Taken together, these findings suggested that treatment with 5-ALA/SFC has a potential therapeutic effect for binge alcohol exposure liver injury in HIV-infected patients.
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Affiliation(s)
- Chi Liu
- Division of Transplantation Immunology, Research Institute, National Center for Child Health and Development, Tokyo, Japan
| | - Ping Zhu
- Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Masayuki Fujino
- Division of Transplantation Immunology, Research Institute, National Center for Child Health and Development, Tokyo, Japan.,AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
| | - Shuoji Zhu
- Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | | | | | | | | | - Jian Zhuang
- Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xiao-Kang Li
- Division of Transplantation Immunology, Research Institute, National Center for Child Health and Development, Tokyo, Japan
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14
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Guix FX, Sartório CL, Ill-Raga G. BACE1 Translation: At the Crossroads Between Alzheimer's Disease Neurodegeneration and Memory Consolidation. J Alzheimers Dis Rep 2019; 3:113-148. [PMID: 31259308 PMCID: PMC6597968 DOI: 10.3233/adr-180089] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Human life unfolds not only in time and space, but also in the recollection and interweaving of memories. Therefore, individual human identity depends fully on a proper access to the autobiographical memory. Such access is hindered under pathological conditions such as Alzheimer’s disease, which affects millions of people worldwide. Unfortunately, no effective cure exists to prevent this disorder, the impact of which will rise alarmingly within the next decades. While Alzheimer’s disease is largely considered to be the outcome of amyloid-β (Aβ) peptide accumulation in the brain, conceiving this complex disorder strictly as the result of Aβ-neurotoxicity is perhaps a too straight-line simplification. Instead, complementary to this view, the tableau of molecular disarrangements in the Alzheimer’s disease brain may be reflecting, at least in part, a loss of function phenotype in memory processing. Here we take BACE1 translation and degradation as a gateway to study molecular mechanisms putatively involved in the transition between memory and neurodegeneration. BACE1 participates in the excision of Aβ-peptide from its precursor holoprotein, but plays a role in synaptic plasticity too. Its translation is governed by eIF2α phosphorylation: a hub integrating cellular responses to stress, but also a critical switch in memory consolidation. Paralleling these dualities, the eIF2α-kinase HRI has been shown to be a nitric oxide-dependent physiological activator of hippocampal BACE1 translation. Finally, beholding BACE1 as a representative protease active in the CNS, we venture a new perspective on the cellular basis of memory, which may incorporate neurodegeneration in itself as a drift in memory consolidating systems.
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Affiliation(s)
- Francesc X Guix
- Department of Molecular Neuropathology, Centro de Biología Molecular Severo Ochoa-CSIC, Madrid, Spain
| | - Carmem L Sartório
- Division of Physiological Sciences, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Gerard Ill-Raga
- Division of Physiological Sciences, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil
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15
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Steiger AK, Zhao Y, Pluth MD. Emerging Roles of Carbonyl Sulfide in Chemical Biology: Sulfide Transporter or Gasotransmitter? Antioxid Redox Signal 2018; 28:1516-1532. [PMID: 28443679 PMCID: PMC5930797 DOI: 10.1089/ars.2017.7119] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 04/16/2017] [Indexed: 12/19/2022]
Abstract
SIGNIFICANCE Carbonyl sulfide (COS) is the most prevalent sulfur-containing gas in the Earth's atmosphere, and it plays important roles in the global sulfur cycle. COS has been implicated in origin of life peptide ligation, is the primary energy source for certain bacteria, and has been detected in mammalian systems. Despite this long and intertwined history with terrestrial biology, limited attention has focused on potential roles of COS as a biological mediator. Recent Advances: Although bacterial COS production is well documented, definitive sources of mammalian COS production have not been confirmed. Enzymatic COS consumption in mammals, however, is well documented and occurs primarily by carbonic anhydrase (CA)-mediated conversion to hydrogen sulfide (H2S). COS has been detected in ex vivo mammalian tissue culture, as well as in exhaled breath as a potential biomarker for different disease pathologies, including cystic fibrosis and organ rejection. Recently, chemical tools for COS delivery have emerged and are poised to advance future investigations into the role of COS in different biological contexts. CRITICAL ISSUES Possible roles of COS as an important biomolecule, gasotransmitter, or sulfide transport intermediate remain to be determined. Key advances in both biological and chemical tools for COS research are needed to further investigate these questions. FUTURE DIRECTIONS Further evaluation of the biological roles of COS and disentangling the chemical biology of COS from that of H2S are needed to further elucidate these interactions. Chemical tools for COS delivery and modulation may provide a first avenue of investigative tools to answer many of these questions. Antioxid. Redox Signal. 28, 1516-1532.
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Affiliation(s)
- Andrea K Steiger
- Department of Chemistry and Biochemistry, Institute of Molecular Biology, Materials Science Institute, University of Oregon , Eugene, Oregon
| | - Yu Zhao
- Department of Chemistry and Biochemistry, Institute of Molecular Biology, Materials Science Institute, University of Oregon , Eugene, Oregon
| | - Michael D Pluth
- Department of Chemistry and Biochemistry, Institute of Molecular Biology, Materials Science Institute, University of Oregon , Eugene, Oregon
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16
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Goto S, Morikawa T, Kubo A, Takubo K, Fukuda K, Kajimura M, Suematsu M. Quantitative imaging mass spectroscopy reveals roles of heme oxygenase-2 for protecting against transhemispheric diaschisis in the brain ischemia. J Clin Biochem Nutr 2018; 63:70-79. [PMID: 30087547 PMCID: PMC6064818 DOI: 10.3164/jcbn.17-136] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 01/09/2018] [Indexed: 11/22/2022] Open
Abstract
Carbon monoxide-generating heme oxygenase-2 is expressed in neurons and plays a crucial role for regulating hypoxic vasodilation through mechanisms unlocking carbon monoxide-dependent inhibition of H2S-generating cystathionine β-synthase expressed in astrocytes. This study aims to examine whether heme oxygenase-2 plays a protective role in mice against stroke. Focal ischemia was induced by middle cerebral artery occlusion. Regional differences in metabolites among ipsilateral and contralateral hemispheres were analysed by quantitative imaging mass spectrometry equipped with an image-processing platform to optimize comparison of local metabolite contents among different animals. Under normoxia, blood flow velocity in precapillary arterioles were significantly elevated in heme oxygenase-2-null mice vs controls, while metabolic intermediates of central carbon metabolism and glutamate synthesis were elevated in the brain of heme oxygenase-2-null mice, suggesting greater metabolic demands to induce hyperemia in these mice. In response to focal ischemia, heme oxygenase-2-null mice exhibited greater regions of ischemic core that coincide with notable decreases in energy metabolism in the contralateral hemisphere as well as in penumbra. In conclusion, these findings suggest that heme oxygenase-2 is involved in mechanisms by which not only protects against compromised energy metabolism of the ipsilateral hemisphere but also ameliorates transhemispheric diaschisis of the contralateral hemisphere in ischemic brain.
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Affiliation(s)
- Shinichi Goto
- Department of Biochemistry, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.,Department of Cardiology, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Takayuki Morikawa
- Department of Biochemistry, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Akiko Kubo
- Department of Biochemistry, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Keiyo Takubo
- Department of Biochemistry, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Keiichi Fukuda
- Department of Cardiology, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Mayumi Kajimura
- Department of Biochemistry, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Makoto Suematsu
- Department of Biochemistry, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan
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17
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Elbirt KK, Bonkovsky HL. Heme Oxygenase: Recent Advances in Understanding Its Regulation and Role. ACTA ACUST UNITED AC 2018. [DOI: 10.1111/paa.1999.111.5.438] [Citation(s) in RCA: 228] [Impact Index Per Article: 32.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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18
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Abstract
Heme oxygenases are composed of two isozymes, Hmox1 and Hmox2, that catalyze the degradation of heme to carbon monoxide (CO), ferrous iron, and biliverdin, the latter of which is subsequently converted to bilirubin. While initially considered to be waste products, CO and biliverdin/bilirubin have been shown over the last 20 years to modulate key cellular processes, such as inflammation, cell proliferation, and apoptosis, as well as antioxidant defense. This shift in paradigm has led to the importance of heme oxygenases and their products in cell physiology now being well accepted. The identification of the two human cases thus far of heme oxygenase deficiency and the generation of mice deficient in Hmox1 or Hmox2 have reiterated a role for these enzymes in both normal cell function and disease pathogenesis, especially in the context of cardiovascular disease. This review covers the current knowledge on the function of both Hmox1 and Hmox2 at both a cellular and tissue level in the cardiovascular system. Initially, the roles of heme oxygenases in vascular health and the regulation of processes central to vascular diseases are outlined, followed by an evaluation of the role(s) of Hmox1 and Hmox2 in various diseases such as atherosclerosis, intimal hyperplasia, myocardial infarction, and angiogenesis. Finally, the therapeutic potential of heme oxygenases and their products are examined in a cardiovascular disease context, with a focus on how the knowledge we have gained on these enzymes may be capitalized in future clinical studies.
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Affiliation(s)
- Anita Ayer
- Vascular Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia; and Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham Veterans Administration Medical Center, Birmingham, Alabama
| | - Abolfazl Zarjou
- Vascular Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia; and Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham Veterans Administration Medical Center, Birmingham, Alabama
| | - Anupam Agarwal
- Vascular Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia; and Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham Veterans Administration Medical Center, Birmingham, Alabama
| | - Roland Stocker
- Vascular Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia; and Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham Veterans Administration Medical Center, Birmingham, Alabama
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19
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Yang D, Peng Y, Ouzhuluobu, Bianbazhuoma, Cui C, Bianba, Wang L, Xiang K, He Y, Zhang H, Zhang X, Liu J, Shi H, Pan Y, Duojizhuoma, Dejiquzong, Cirenyangji, Baimakangzhuo, Gonggalanzi, Liu S, Gengdeng, Wu T, Chen H, Qi X, Su B. HMOX2 Functions as a Modifier Gene for High-Altitude Adaptation in Tibetans. Hum Mutat 2015; 37:216-23. [PMID: 26781569 DOI: 10.1002/humu.22935] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 11/16/2015] [Indexed: 12/21/2022]
Abstract
Tibetans are well adapted to high-altitude environments. Among the adaptive traits in Tibetans, the relatively low hemoglobin level is considered a blunted erythropoietic response to hypoxic challenge. Previously, EPAS1 and EGLN1, the major upstream regulators in the hypoxic pathway, were reportedly involved in the hemoglobin regulation in Tibetans. In this study, we report a downstream gene (HMOX2) involved in heme catabolism, which harbors potentially adaptive variants in Tibetans. We first resequenced the entire genomic region (45.6 kb) of HMOX2 in Tibetans, which confirmed the previously suspected signal of positive selection on HMOX2 in Tibetans. Subsequent association analyses of hemoglobin levels in two independent Tibetan populations (a total of 1,250 individuals) showed a male-specific association between the HMOX2 variants and hemoglobin levels. Tibetan males with the derived C allele at rs4786504:T>C displayed lower hemoglobin level as compared with the T allele carriers. Furthermore, our in vitro experiments indicated that the C allele of rs4786504 could increase the expression of HMOX2, presumably leading to a more efficient breakdown of heme that may help maintain a relatively low hemoglobin level at high altitude. Collectively, we propose that HMOX2 contributes to high-altitude adaptation in Tibetans by functioning as a modifier in the regulation of hemoglobin metabolism.
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Affiliation(s)
- Deying Yang
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.,Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yi Peng
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China
| | - Ouzhuluobu
- High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, 850000, China
| | - Bianbazhuoma
- The Municipal People's Hospital of Lhasa, Lhasa, 850000, Tibet, China
| | - Chaoying Cui
- High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, 850000, China
| | - Bianba
- High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, 850000, China
| | - Liangbang Wang
- National Key Laboratory of High Altitude Medicine, High Altitude Medical Research Institute, Xining, 810012, China
| | - Kun Xiang
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China
| | - Yaoxi He
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.,Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Hui Zhang
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China
| | - Xiaoming Zhang
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China
| | - Jiewei Liu
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.,Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Hong Shi
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.,Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China
| | - Yongyue Pan
- High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, 850000, China
| | - Duojizhuoma
- High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, 850000, China
| | - Dejiquzong
- High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, 850000, China
| | - Cirenyangji
- High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, 850000, China
| | - Baimakangzhuo
- High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, 850000, China
| | - Gonggalanzi
- High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, 850000, China
| | - Shimin Liu
- National Key Laboratory of High Altitude Medicine, High Altitude Medical Research Institute, Xining, 810012, China
| | - Gengdeng
- National Key Laboratory of High Altitude Medicine, High Altitude Medical Research Institute, Xining, 810012, China
| | - Tianyi Wu
- National Key Laboratory of High Altitude Medicine, High Altitude Medical Research Institute, Xining, 810012, China
| | - Hua Chen
- Center for Computational Genomics, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Xuebin Qi
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China
| | - Bing Su
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China
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20
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Grubišić V, Kennedy AJ, Sweatt JD, Parpura V. Pitt-Hopkins Mouse Model has Altered Particular Gastrointestinal Transits In Vivo. Autism Res 2015; 8:629-33. [PMID: 25728630 PMCID: PMC5724775 DOI: 10.1002/aur.1467] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2014] [Accepted: 02/04/2015] [Indexed: 12/31/2022]
Abstract
Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder, classified as an autism spectrum disorder that is caused by the haploinsufficiency of Transcription Factor 4 (TCF4). The most common non-neurological symptoms in PTHS patients are gastrointestinal (GI) disturbances, mainly gastroesophageal reflux and severe constipation (in about 30 and 75% of PTHS patients, respectively). We hypothesized that the recently recognized mouse model of PTHS will exhibit problems with their gut function. We conducted series of in vivo tests on 15- to 19- week old male mice, heterozygous for the TCF4 functional deletion, mimicking the TCF4 haploinsufficiency in PTHS patients, and their wild type littermates. Data collection and initial analysis were performed blindly, that is, the genotyping key was received after the mean values were calculated for each individual animal, and then mean/median of each group was subsequently calculated. Body weight, fecal pellet output, and fluid content were similar between the groups, indicating normal gross growth of PTHS mice and their overall physiological GI motility and intestinal secretion/absorption. There were no significant differences in gut length and gross appearance pointing out that PTHS mice have normal gut in gross anatomical terms. However, the assessment of gut transit indicates that, while whole-gut transit velocity was similar between the groups, the upper GI and distal colon transit velocities were significantly reduced in the PTHS mice. This is the first evidence of specific gut related problems in the PTHS mice. Our study also validates the TCF4 functional knockout mice as an animal model to study PTHS-associated GI disturbances.
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Affiliation(s)
- Vladimir Grubišić
- Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Andrew J Kennedy
- Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama
| | - J David Sweatt
- Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Vladimir Parpura
- Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama
- Department of Biotechnology, University of Rijeka, Rijeka, Croatia
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21
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Schallner N, Pandit R, LeBlanc R, Thomas AJ, Ogilvy CS, Zuckerbraun BS, Gallo D, Otterbein LE, Hanafy KA. Microglia regulate blood clearance in subarachnoid hemorrhage by heme oxygenase-1. J Clin Invest 2015; 125:2609-25. [PMID: 26011640 DOI: 10.1172/jci78443] [Citation(s) in RCA: 159] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Accepted: 04/27/2015] [Indexed: 12/25/2022] Open
Abstract
Subarachnoid hemorrhage (SAH) carries a 50% mortality rate. The extravasated erythrocytes that surround the brain contain heme, which, when released from damaged red blood cells, functions as a potent danger molecule that induces sterile tissue injury and organ dysfunction. Free heme is metabolized by heme oxygenase (HO), resulting in the generation of carbon monoxide (CO), a bioactive gas with potent immunomodulatory capabilities. Here, using a murine model of SAH, we demonstrated that expression of the inducible HO isoform (HO-1, encoded by Hmox1) in microglia is necessary to attenuate neuronal cell death, vasospasm, impaired cognitive function, and clearance of cerebral blood burden. Initiation of CO inhalation after SAH rescued the absence of microglial HO-1 and reduced injury by enhancing erythrophagocytosis. Evaluation of correlative human data revealed that patients with SAH have markedly higher HO-1 activity in cerebrospinal fluid (CSF) compared with that in patients with unruptured cerebral aneurysms. Furthermore, cisternal hematoma volume correlated with HO-1 activity and cytokine expression in the CSF of these patients. Collectively, we found that microglial HO-1 and the generation of CO are essential for effective elimination of blood and heme after SAH that otherwise leads to neuronal injury and cognitive dysfunction. Administration of CO may have potential as a therapeutic modality in patients with ruptured cerebral aneurysms.
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22
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Yetik-Anacak G, Sorrentino R, Linder AE, Murat N. Gas what: NO is not the only answer to sexual function. Br J Pharmacol 2014; 172:1434-54. [PMID: 24661203 DOI: 10.1111/bph.12700] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Revised: 02/18/2014] [Accepted: 03/17/2014] [Indexed: 01/08/2023] Open
Abstract
The ability to get and keep an erection is important to men for several reasons and the inability is known as erectile dysfunction (ED). ED has started to be accepted as an early indicator of systemic endothelial dysfunction and subsequently of cardiovascular diseases. The role of NO in endothelial relaxation and erectile function is well accepted. The discovery of NO as a small signalling gasotransmitter led to the investigation of the role of other endogenously derived gases, carbon monoxide (CO) and hydrogen sulphide (H2 S) in physiological and pathophysiological conditions. The role of NO and CO in sexual function and dysfunction has been investigated more extensively and, recently, the involvement of H2 S in erectile function has also been confirmed. In this review, we focus on the role of these three sister gasotransmitters in the physiology, pharmacology and pathophysiology of sexual function in man, specifically erectile function. We have also reviewed the role of soluble guanylyl cyclase/cGMP pathway as a common target of these gasotransmitters. Several studies have proposed alternative therapies targeting different mechanisms in addition to PDE-5 inhibition for ED treatment, since some patients do not respond to these drugs. This review highlights complementary and possible coordinated roles for these mediators and treatments targeting these gasotransmitters in erectile function/ED.
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Affiliation(s)
- G Yetik-Anacak
- Department of Pharmacology, Faculty of Pharmacy, Ege University, İzmir, Turkey
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23
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Abstract
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) remain major causes of morbidity and mortality in critical care medicine despite advances in therapeutic modalities. ALI can be associated with sepsis, trauma, pharmaceutical or xenobiotic exposures, high oxygen therapy (hyperoxia), and mechanical ventilation. Of the small gas molecules (NO, CO, H₂S) that arise in human beings from endogenous enzymatic activities, the physiological significance of NO is well established, whereas that of CO or H₂S remains controversial. Recent studies have explored the potential efficacy of inhalation therapies using these small gas molecules in animal models of ALI. NO has vasoregulatory and redox-active properties and can function as a selective pulmonary vasodilator. Inhaled NO (iNO) has shown promise as a therapy in animal models of ALI including endotoxin challenge, ischemia/reperfusion (I/R) injury, and lung transplantation. CO, another diatomic gas, can exert cellular tissue protection through antiapoptotic, anti-inflammatory, and antiproliferative effects. CO has shown therapeutic potential in animal models of endotoxin challenge, oxidative lung injury, I/R injury, pulmonary fibrosis, ventilator-induced lung injury, and lung transplantation. H₂S, a third potential therapeutic gas, can induce hypometabolic states in mice and can confer both pro- and anti-inflammatory effects in rodent models of ALI and sepsis. Clinical studies have shown variable results for the efficacy of iNO in lung transplantation and failure for this therapy to improve mortality in ARDS patients. No clinical studies have been conducted with H₂S. The clinical efficacy of CO remains unclear and awaits further controlled clinical studies in transplantation and sepsis.
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Affiliation(s)
- Stefan W Ryter
- Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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24
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Gibbons SJ, Verhulst PJ, Bharucha A, Farrugia G. Review article: carbon monoxide in gastrointestinal physiology and its potential in therapeutics. Aliment Pharmacol Ther 2013; 38:689-702. [PMID: 23992228 PMCID: PMC3788684 DOI: 10.1111/apt.12467] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Revised: 05/03/2013] [Accepted: 08/07/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND While carbon monoxide (CO) is a known toxin, it is now recognised that CO is also an important signalling molecule involved in physiology and pathophysiology. AIMS To summarise our current understanding of the role of endogenous CO in the regulation of gastrointestinal physiology and pathophysiology, and to potential therapeutic applications of modulating CO. METHODS This review is based on a comprehensive search of the Ovid Medline comprehensive database and supplemented by our ongoing studies evaluating the role of CO in gastrointestinal physiology and pathophysiology. RESULTS Carbon monoxide derived from haem oxygenase (HO)-2 is predominantly involved in neuromodulation and in setting the smooth muscle membrane potential, while CO derived from HO-1 has anti-inflammatory and antioxidative properties, which protect gastrointestinal smooth muscle from damage caused by injury or inflammation. Exogenous CO is being explored as a therapeutic agent in a variety of gastrointestinal disorders, including diabetic gastroparesis, post-operative ileus, organ transplantation, inflammatory bowel disease and sepsis. However, identifying the appropriate mechanism for safely delivering CO in humans is a major challenge. CONCLUSIONS Carbon monoxide is an important regulator of gastrointestinal function and protects the gastrointestinal tract against noxious injury. CO is a promising therapeutic target in conditions associated with gastrointestinal injury and inflammation. Elucidating the mechanisms by which CO works and developing safe CO delivery mechanisms are necessary to refine therapeutic strategies.
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Affiliation(s)
- S J Gibbons
- Enteric NeuroScience Program, Mayo Clinic, Rochester, MN 55905, USA
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25
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Hemin and Zinc Protoporphyrin IX Affect Granisetron Constipating Effects In Vitro and In Vivo. ISRN GASTROENTEROLOGY 2013; 2013:612037. [PMID: 23864955 PMCID: PMC3705784 DOI: 10.1155/2013/612037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/24/2013] [Accepted: 06/05/2013] [Indexed: 12/20/2022]
Abstract
Granisetron is a 5-HT3 receptors antagonist used in the management of emesis associated with anticancer chemotherapy. It affects intestinal motility with constipating effect. Since the pathway heme oxygenase/carbon monoxide (HO/CO) is involved in gastrointestinal motility, we evaluated the possible interplay between granisetron and agents affecting HO/CO pathways such as zinc protoporphyrin IX (ZnPPIX), an HO inhibitor, or hemin, an HO-1 inducer. ZnPPIX (10 µM) or hemin (10 µM), but not granisetron (0.1, 0.3, 1 µM), affected spontaneous basal activity recorded in rat duodenal strips, in noncholinergic nonadrenergic conditions. Granisetron restored spontaneous basal activity after ZnPPIX, but not after hemin. ZnPPIX decreased and hemin increased the inhibition of activity after electrical field stimulation (EFS), but they did not affect the contraction that follows the relaxation induced by EFS called off contraction. Granisetron did not alter the response to EFS per se but abolished both ZnPPIX and hemin effect when coadministered. In vivo study showed constipating effect of granisetron (25, 50, 75 µg/kg/sc) but no effect of either ZnPPIX (50 µg/kg/i.p.) or hemin (50 µM/kg/i.p.). When coadministered, granisetron effect was abolished by ZnPPIX and increased by hemin. Specimens from rats treated in vivo with hemin (50 µM/kg/i.p.) showed increased HO-1 protein levels. In conclusion, granisetron seems to interact with agents affecting HO/CO pathway both in vitro and in vivo.
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Schulz S, Wong RJ, Jang KY, Kalish F, Chisholm KM, Zhao H, Vreman HJ, Sylvester KG, Stevenson DK. Heme oxygenase-1 deficiency promotes the development of necrotizing enterocolitis-like intestinal injury in a newborn mouse model. Am J Physiol Gastrointest Liver Physiol 2013; 304:G991-G1001. [PMID: 23578787 PMCID: PMC3680684 DOI: 10.1152/ajpgi.00363.2012] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2012] [Accepted: 04/09/2013] [Indexed: 01/31/2023]
Abstract
Necrotizing enterocolitis (NEC) is typified by mucosal destruction, which subsequently can lead to intestinal necrosis. Prematurity, enteral feeding, and bacterial colonization are the main risk factors and, combined with other stressors, can cause increased intestinal permeability, injury, and an exaggerated inflammatory response. Heme oxygenase-1 (HO-1) mediates intestinal protection due to anti-inflammatory, antioxidative, and antiapoptotic effects of its products carbon monoxide, biliverdin, and bilirubin. This study investigates a possible role of HO-1 in the pathogenesis of NEC using a newborn mouse model. We induced NEC-like intestinal injury in 7-day-old HO-1 heterozygous (HO-1 Het, Hmox1(+/-)) and wild-type (Wt, Hmox1(+/+)) mice by gavage feeding and hypoxic exposures. Control (Con) pups of both genotypes were dam-fed. Intestines of HO-1 Het Con pups appeared predisposed to injury, with higher histological damage scores, more TUNEL-positive cells, and a significant reduction in muscularis externa thickness compared with Wt Con pups. The increase in HO activity after HO-1 induction by the substrate heme or by hypoxic stress was significantly impaired in HO-1 Het pups. After induction of intestinal injury, HO-1 Het pups displayed significantly higher NEC incidence (78 vs. 43%), mortality (83 vs. 54%), and median scores (2.5 vs. 1.5) than Wt NEC pups. PCR array analyses revealed increased expressions of IL-1β, P-selectin, matrix metallopeptidase 2, collagen type XVIII-α1, serpine 1, and others in NEC-induced HO-1 Het ileal and jejunal tissues. We conclude that a partial HO-1 deficiency promotes experimental NEC-like intestinal injury, possibly mediated by exaggerated inflammation and disruption in tissue repair.
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Affiliation(s)
- Stephanie Schulz
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
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Zhou J, Wu PF, Wang F, Chen JG. Targeting gaseous molecules to protect against cerebral ischaemic injury: mechanisms and prospects. Clin Exp Pharmacol Physiol 2013; 39:566-76. [PMID: 22150768 DOI: 10.1111/j.1440-1681.2011.05654.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
1. Ischaemic brain injury is a leading cause of death and disability in many countries. However, the pathological mechanisms underlying ischaemic brain injury, including oxidative stress, calcium overload, excitotoxicity and neuronal apoptosis, are perplexing and this makes it difficult to find effective novel drugs for the treatment of the condition. 2. Recently, gaseous molecules such as nitric oxide (NO), carbon monoxide (CO), hydrogen sulphide (H(2)S) and hydrogen (H(2)) have attracted considerable interest because of their physiological and pathophysiological roles in various body systems. Emerging evidence indicates that gaseous molecules are involved in the pathological processes of ischaemic brain damage. 3. In the present review, we summarize evidence regarding the involvement of gaseous molecules in ischaemic brain injury and discuss the therapeutic potential of targeting gaseous molecules. 4. Collectively, the available data suggest that the application of these biological gas molecules and their pharmacological regulators may be a potential therapeutic approach for the treatment of ischaemic brain injury.
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Affiliation(s)
- Jun Zhou
- Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, #13 Hangkong Road, Wuhan, Hubei 430030, China
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Bonkovsky HL, Hou W, Steuerwald N, Tian Q, Li T, Parsons J, Hamilton A, Hwang S, Schrum L. Heme status affects human hepatic messenger RNA and microRNA expression. World J Gastroenterol 2013; 19:1593-601. [PMID: 23538684 PMCID: PMC3602476 DOI: 10.3748/wjg.v19.i10.1593] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Revised: 11/06/2012] [Accepted: 12/15/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess effects of heme on messenger RNA (mRNA) and microRNA (miRNA) profiles of liver cells derived from humans.
METHODS: We exposed human hepatoma cell line Huh-7 cells to excess iron protoporphyrin (heme) (10 μmol/L) or induced heme deficiency by addition of 4, 6-dioxoheptanoic acid (500 μmol/L), a potent inhibitor of aminolevulinic acid dehydratase, for 6 h or 24 h. We harvested total RNA from the cells and performed both mRNA and miRNA array analyses, with use of Affymetrix chips, reagents, and instruments (human genome U133 plus 2.0 and miRNA 2.0 arrays). We assessed changes and their significance and interrelationships with Target Scan, Pathway Studios, and Ingenuity software.
RESULTS: Changes in mRNA levels were most numerous and striking at 6 h after heme treatment but were similar and still numerous at 24 h. After 6 h of heme exposure, the increase in heme oxygenase 1 gene expression was 60-fold by mRNA and 88-fold by quantitative reverse transcription-polymerase chain reaction. We found striking changes, especially up-regulation by heme of nuclear erythroid-2 related factor-mediated oxidative stress responses, protein ubiquitination, glucocorticoid signaling, P53 signaling, and changes in RNAs that regulate intermediary metabolism. Fewer mRNAs were down-regulated by heme, and the fold decreases were less exuberant than were the increases. Notable decreases after 24 h of heme exposure were patatin-like phospholipase domain-containing protein 3 (-6.5-fold), neuronal PAS domain protein 2 (-1.93-fold), and protoporphyrinogen oxidase (-1.7-fold).
CONCLUSION: Heme excess exhibits several toxic effects on liver and kidney, which deserve study in humans and in animal models of the human porphyrias or other disorders.
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Abstract
Carbon monoxide (CO), a low molecular weight gas, is a ubiquitous environmental product of organic combustion, which is also produced endogenously in the body, as the byproduct of heme metabolism. CO binds to hemoglobin, resulting in decreased oxygen delivery to bodily tissues at toxicological concentrations. At physiological concentrations, CO may have endogenous roles as a potential signaling mediator in vascular function and cellular homeostasis. Exhaled CO (eCO), similar to exhaled nitric oxide (eNO), has been evaluated as a candidate breath biomarker of pathophysiological states, including smoking status, and inflammatory diseases of the lung and other organs. eCO values have been evaluated as potential indicators of inflammation in asthma, stable COPD and exacerbations, cystic fibrosis, lung cancer, or during surgery or critical care. The utility of eCO as a marker of inflammation and its potential diagnostic value remain incompletely characterized. Among other candidate 'medicinal gases' with therapeutic potential, (e.g., NO and H2S), CO has been shown to act as an effective anti-inflammatory agent in preclinical animal models of inflammatory disease, acute lung injury, sepsis, ischemia/reperfusion injury and organ graft rejection. Current and future clinical trials will evaluate the clinical applicability of this gas as a biomarker and/or therapeutic in human disease.
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Affiliation(s)
- Stefan W Ryter
- Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
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Madeira JM, Gibson DL, Kean WF, Klegeris A. The biological activity of auranofin: implications for novel treatment of diseases. Inflammopharmacology 2012; 20:297-306. [PMID: 22965242 DOI: 10.1007/s10787-012-0149-1] [Citation(s) in RCA: 126] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2012] [Accepted: 08/22/2012] [Indexed: 11/30/2022]
Abstract
More than 30 years ago, auranofin was developed for the treatment of rheumatoid arthritis as a substitution for the injectable gold compounds aurothiomalate and aurothioglucose. Both the ease of oral administration over intramuscular injections and more potent anti-inflammatory effects in vitro made auranofin seem like an excellent substitute for the traditional injectable gold compounds. Despite efficacy in the treatment of both rheumatoid arthritis and psoriasis, currently, auranofin is seldom used as a treatment for patients with rheumatoid arthritis as more novel anti-rheumatic medications have become available. Despite the decline in its clinical applications, research on auranofin has continued as it shows promise in the treatment of several different diseases. In recent years, advances in technology have allowed researchers to use molecular techniques to identify novel mechanisms of action of auranofin. Additionally, researchers are discovering potential new applications of auranofin. Dual inhibition of inflammatory pathways and thiol redox enzymes by auranofin makes it a new candidate for cancer therapy and treating microbial infections. This review will summarize recently obtained data on the mechanisms of action of auranofin, and potential new applications of auranofin in the treatment of various diseases, including several types of leukaemia, carcinomas, and parasitic, bacterial, and viral infections.
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Affiliation(s)
- J M Madeira
- Department of Biology, Irving K. Barber School of Arts and Sciences, University of British Columbia Okanagan Campus, Kelowna, BC, Canada
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31
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Varfaj F, Lampe JN, Ortiz de Montellano PR. Role of cysteine residues in heme binding to human heme oxygenase-2 elucidated by two-dimensional NMR spectroscopy. J Biol Chem 2012; 287:35181-35191. [PMID: 22923613 DOI: 10.1074/jbc.m112.378042] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Human heme oxygenases 1 and 2 (HO-1 and HO-2) degrade heme in the presence of oxygen and NADPH-cytochrome P450 reductase, producing ferrous iron, CO, and biliverdin. HO-1 is an inducible enzyme, but HO-2 is constitutively expressed in selected tissues and is involved in signaling and regulatory processes. HO-2 has three cysteine residues that have been proposed to modulate the affinity for heme, whereas HO-1 has none. Here we use site-specific mutagenesis and two-dimensional NMR of l-[3-(13)C]cysteine-labeled proteins to determine the redox state of the individual cysteines in HO-2 and assess their roles in binding of heme. The results indicate that in the apoprotein, Cys(282) and Cys(265) are in the oxidized state, probably in an intramolecular disulfide bond. The addition of a reducing agent converts them to the reduced, free thiol state. Two-dimensional NMR of site-specific mutants reveals that the redox state of Cys(265) and Cys(282) varies with the presence or absence of other Cys residues, indicating that the microenvironments of the Cys residues are mutually interdependent. Cys(265) appears to be in a relatively hydrophilic, oxidizable environment compared with Cys(127) and Cys(282). Chemical shift data indicate that none of the cysteines stably coordinates to the heme iron atom. In the oxidized state of the apoprotein, heme is bound 2.5-fold more tightly than in the reduced state. This small difference in heme affinity between the oxidized and reduced states of the protein is much less than previously reported, suggesting that it is not a significant factor in the physiological regulation of cellular heme levels.
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Affiliation(s)
- Fatbardha Varfaj
- Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, California 94158-2517
| | - Jed N Lampe
- Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, California 94158-2517
| | - Paul R Ortiz de Montellano
- Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, California 94158-2517.
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Abstract
Hydrogen sulfide (H(2)S) has recently emerged as a mammalian gaseous messenger molecule, akin to nitric oxide and carbon monoxide. H(2)S is predominantly formed from Cys or its derivatives by the enzymes cystathionine β-synthase and cystathionine γ-lyase. One of the mechanisms by which H(2)S signals is by sulfhydration of reactive Cys residues in target proteins. Although analogous to protein nitrosylation, sulfhydration is substantially more prevalent and usually increases the catalytic activity of targeted proteins. Physiological actions of sulfhydration include the regulation of inflammation and endoplasmic reticulum stress signalling as well as of vascular tension.
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Affiliation(s)
- Bindu D Paul
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
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Crystallographic studies of heme oxygenase complexed with an unstable reaction intermediate, verdoheme. J Inorg Biochem 2012; 113:102-9. [PMID: 22673156 DOI: 10.1016/j.jinorgbio.2012.04.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2012] [Revised: 04/05/2012] [Accepted: 04/11/2012] [Indexed: 11/20/2022]
Abstract
This article discusses the accuracy of X-ray structural studies of heme oxygenase (HO) in complex with an unstable intermediate, verdoheme. Heme degradation by HO proceeds through three successive steps of O(2) activation. The mechanism of the third step, the ring opening of verdoheme, has been the least understood. Recent structural studies of the verdoheme-HO complex provide detailed information concerning this mechanism. Due to X-ray-induced photoreduction and the instability of verdoheme, it has been difficult to obtain an accurate structure for the ferrous verdoheme-HO complex. Therefore, accurate structural studies, including analysis of the electronic state of the verdoheme-HO complex, are needed to elucidate the proper reaction mechanism.
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Hypoxic regulation of the cerebral microcirculation is mediated by a carbon monoxide-sensitive hydrogen sulfide pathway. Proc Natl Acad Sci U S A 2012; 109:1293-8. [PMID: 22232681 DOI: 10.1073/pnas.1119658109] [Citation(s) in RCA: 204] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Enhancement of cerebral blood flow by hypoxia is critical for brain function, but signaling systems underlying its regulation have been unclear. We report a pathway mediating hypoxia-induced cerebral vasodilation in studies monitoring vascular disposition in cerebellar slices and in intact mouse brains using two-photon intravital laser scanning microscopy. In this cascade, hypoxia elicits cerebral vasodilation via the coordinate actions of H(2)S formed by cystathionine β-synthase (CBS) and CO generated by heme oxygenase (HO)-2. Hypoxia diminishes CO generation by HO-2, an oxygen sensor. The constitutive CO physiologically inhibits CBS, and hypoxia leads to increased levels of H(2)S that mediate the vasodilation of precapillary arterioles. Mice with targeted deletion of HO-2 or CBS display impaired vascular responses to hypoxia. Thus, in intact adult brain cerebral cortex of HO-2-null mice, imaging mass spectrometry reveals an impaired ability to maintain ATP levels on hypoxia.
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De Benedictis L, Potenza MA, Gagliardi S, Zigrino A, Montagnani M, De Salvia MA. Rosiglitazone reverses increased duodenal inhibitory response in spontaneously hypertensive rats. Neurogastroenterol Motil 2012; 24:e56-66. [PMID: 21995307 DOI: 10.1111/j.1365-2982.2011.01798.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Thiazolidinediones (TZDs) including rosiglitazone (ROSI) are insulin sensitizing agents with beneficial gastrointestinal effects. However, no studies are available on TZDs effect in gastrointestinal motility. We evaluated the effects of ROSI on gastrointestinal inhibitory neurotransmission focusing on the modulatory roles of nitric oxide synthase/nitric oxide (NOS/NO) and heme oxygenase/carbon monoxide (HO/CO) pathways. METHODS Spontaneously hypertensive rats (SHR) were used as model of insulin resistance. Duodenal strips were obtained from vehicle-treated SHR, ROSI-treated SHR (5 mg kg(-1) by gavage daily per 6 weeks), and Wistar Kyoto (WKY). Inhibitory responses to electrical field stimulation (EFS) were evaluated in the presence of HO inhibitor zinc protoporphyrin IX (ZnPPIX, 10 μmol L(-1)) or NOS inhibitor N(G)-nitro-L-arginine (L-NNA, 100 μmol L(-1)), alone and in combination. Protein levels of HO and NOS isoforms were evaluated by immunohistochemistry and western blot analysis. KEY RESULTS Basal responses to EFS were significantly increased in duodenum strips from vehicle-treated SHR vs WKY. This effect was reversed in ROSI-treated SHR. The EFS-mediated relaxation was comparably reduced by ZnPPIX in WKY and SHR, but not in ROSI-treated SHR animals. The L-NNA reduced EFS response to a similar extent in WKY and ROSI -treated SHR, but its effect was significantly higher in vehicle-treated SHR. Expression of HO-1 protein was significantly lower, whereas HO-2 protein levels were unchanged in ROSI-treated SHR with respect to vehicle-treated SHR. Finally, increased levels of nNOS in vehicle-treated SHR were reduced in ROSI-treated SHR. CONCLUSIONS & INFERENCES Chronic ROSI treatment reverses increased SHR duodenal inhibitory response acting on CO and NO components.
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Affiliation(s)
- L De Benedictis
- Department of Biomedical Sciences and Human Oncology, Medical School, University of Bari Aldo Moro, Bari, Italy
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36
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Gullotta F, di Masi A, Coletta M, Ascenzi P. CO metabolism, sensing, and signaling. Biofactors 2012; 38:1-13. [PMID: 22213392 DOI: 10.1002/biof.192] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2011] [Accepted: 10/19/2011] [Indexed: 12/16/2022]
Abstract
CO is a colorless and odorless gas produced by the incomplete combustion of hydrocarbons, both of natural and anthropogenic origin. Several microorganisms, including aerobic and anaerobic bacteria and anaerobic archaea, use exogenous CO as a source of carbon and energy for growth. On the other hand, eukaryotic organisms use endogenous CO, produced during heme degradation, as a neurotransmitter and as a signal molecule. CO sensors act as signal transducers by coupling a "regulatory" heme-binding domain to a "functional" signal transmitter. Although high CO concentrations inhibit generally heme-protein actions, low CO levels can influence several signaling pathways, including those regulated by soluble guanylate cyclase and/or mitogen-activated protein kinases. This review summarizes recent insights into CO metabolism, sensing, and signaling.
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Affiliation(s)
- Francesca Gullotta
- Department of Experimental Medicine and Biochemical Sciences, University of Roma Tor Vergata, Via Montpellier 1, I-00133 Roma, Italy
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Gerjevic LN, Lu S, Chaky JP, Harrison-Findik DD. Regulation of heme oxygenase expression by alcohol, hypoxia and oxidative stress. World J Biol Chem 2011; 2:252-60. [PMID: 22216371 PMCID: PMC3247681 DOI: 10.4331/wjbc.v2.i12.252] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2011] [Revised: 10/11/2011] [Accepted: 10/17/2011] [Indexed: 02/05/2023] Open
Abstract
AIM: To study the effect of both acute and chronic alcohol exposure on heme oxygenases (HOs) in the brain, liver and duodenum.
METHODS: Wild-type C57BL/6 mice, heterozygous Sod2 knockout mice, which exhibit attenuated manganese superoxide dismutase activity, and liver-specific ARNT knockout mice were used to investigate the role of alcohol-induced oxidative stress and hypoxia. For acute alcohol exposure, ethanol was administered in the drinking water for 1 wk. Mice were pair-fed with regular or ethanol-containing Lieber De Carli liquid diets for 4 wk for chronic alcohol studies. HO expression was analyzed by real-time quantitative polymerase chain reaction and Western blotting.
RESULTS: Chronic alcohol exposure downregulated HO-1 expression in the brain but upregulated it in the duodenum of wild-type mice. It did not alter liver HO-1 expression, nor HO-2 expression in the brain, liver or duodenum. In contrast, acute alcohol exposure decreased both liver HO-1 and HO-2 expression, and HO-2 expression in the duodenum of wild-type mice. The decrease in liver HO-1 expression was abolished in ARNT+/- mice. Sod2+/- mice with acute alcohol exposure did not exhibit any changes in liver HO-1 and HO-2 expression or in brain HO-2 expression. However, alcohol inhibited brain HO-1 and duodenal HO-2 but increased duodenal HO-1 expression in Sod2+/- mice. Collectively, these findings indicate that acute and chronic alcohol exposure regulates HO expression in a tissue-specific manner. Chronic alcohol exposure alters brain and duodenal, but not liver HO expression. However, acute alcohol exposure inhibits liver HO-1 and HO-2, and also duodenal HO-2 expression.
CONCLUSION: The inhibition of liver HO expression by acute alcohol-induced hypoxia may play a role in the early phases of alcoholic liver disease progression.
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Affiliation(s)
- Lisa Nicole Gerjevic
- Lisa Nicole Gerjevic, Sizhao Lu, Jonathan Pascal Chaky, Duygu Dee Harrison-Findik, Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5820, United States
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Abstract
Scientific styles vary tremendously. For me, research is largely about the unfettered pursuit of novel ideas and experiments that can test multiple ideas in a day, not a year, an approach that I learned from my mentor Julius "Julie" Axelrod. This focus on creative conceptualizations has been my métier since working in the summers during medical school at the National Institutes of Health, during my two years in the Axelrod laboratory, and throughout my forty-five years at Johns Hopkins University School of Medicine. Equally important has been the "high" that emerges from brainstorming with my students. Nothing can compare with the eureka moments when, together, we sense new insights and, better yet, when high-risk, high-payoff experiments succeed. Although I have studied many different questions over the years, a common theme emerges: simple biochemical approaches to understanding molecular messengers, usually small molecules. Equally important has been identifying, purifying, and cloning the messengers' relevant biosynthetic, degradative, or target proteins, at all times seeking potential therapeutic relevance in the form of drugs. In the interests of brevity, this Reflections article is highly selective, and, with a few exceptions, literature citations are only of findings of our laboratory that illustrate notable themes.
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Affiliation(s)
- Solomon H Snyder
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
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Leffler CW, Parfenova H, Jaggar JH. Carbon monoxide as an endogenous vascular modulator. Am J Physiol Heart Circ Physiol 2011; 301:H1-H11. [PMID: 21498777 DOI: 10.1152/ajpheart.00230.2011] [Citation(s) in RCA: 116] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Carbon monoxide (CO) is produced by heme oxygenase (HO)-catalyzed heme degradation to CO, iron, and biliverdin. HO has two active isoforms, HO-1 (inducible) and HO-2 (constitutive). HO-2, but not HO-1, is highly expressed in endothelial and smooth muscle cells and in adjacent astrocytes in the brain. HO-1 is expressed basally only in the spleen and liver but can be induced to a varying extent in most tissues. Elevating heme, protein phosphorylation, Ca(2+) influx, and Ca(2+)/calmodulin-dependent processes increase HO-2 activity. CO dilates cerebral arterioles and may constrict or dilate skeletal muscle and renal arterioles. Selected vasodilatory stimuli, including seizures, glutamatergic stimulation, hypoxia, hypotension, and ADP, increase CO, and the inhibition of HO attenuates the dilation to these stimuli. Astrocytic HO-2-derived CO causes glutamatergic dilation of pial arterioles. CO dilates by activating smooth muscle cell large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels. CO binds to BK(Ca) channel-bound heme, leading to an increase in Ca(2+) sparks-to-BK(Ca) channel coupling. Also, CO may bind directly to the BK(Ca) channel at several locations. Endothelial nitric oxide and prostacyclin interact with HO/CO in circulatory regulation. In cerebral arterioles in vivo, in contrast to dilation to acute CO, a prolonged exposure of cerebral arterioles to elevated CO produces progressive constriction by inhibiting nitric oxide synthase. The HO/CO system is highly protective to the vasculature. CO suppresses apoptosis and inhibits components of endogenous oxidant-generating pathways. Bilirubin is a potent reactive oxygen species scavenger. Still many questions remain about the physiology and biochemistry of HO/CO in the circulatory system and about the function and dysfunction of this gaseous mediator system.
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Abstract
This review focuses on thiol/disulfide redox switches that regulate heme binding to proteins and modulate their activities. The importance of redox switches in metabolic regulation and the general mechanism by which redox switches modulate activity are discussed. Methods are described to characterize heme-binding sites and to assess their physiological relevance. For thiol/disulfide interconversion to regulate activity of a system, the redox process must be reversible at the ambient redox potentials found within the cell; thus, methods (and their limitations) are discussed that can address the physiological relevance of a redox switch. We review recent results that define a mechanism for how thiol/disulfide redox switches that control heme binding can regulate the activities of an enzyme, heme oxygenase-2, and an ion channel, the BK potassium channel. The redox switches on these proteins are composed of different types of Cys-containing motifs that have opposite effects on heme affinity, yet have complementary effects on hypoxia sensing. Finally, a model is proposed to describe how the redox switches on heme oxygenase-2 and the BK channel form an interconnected system that is poised to sense oxygen levels in the bloodstream and to elicit the hypoxic response when oxygen levels drop below a threshold value.
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Affiliation(s)
- Stephen W Ragsdale
- Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109-0606, USA.
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Choi YK, Kim CK, Lee H, Jeoung D, Ha KS, Kwon YG, Kim KW, Kim YM. Carbon monoxide promotes VEGF expression by increasing HIF-1alpha protein level via two distinct mechanisms, translational activation and stabilization of HIF-1alpha protein. J Biol Chem 2010; 285:32116-25. [PMID: 20724477 DOI: 10.1074/jbc.m110.131284] [Citation(s) in RCA: 124] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Carbon monoxide (CO) plays a significant role in vascular functions. We here examined the molecular mechanism by which CO regulates HIF-1 (hypoxia-inducible transcription factor-1)-dependent expression of vascular endothelial growth factor (VEGF), which is an important angiogenic factor. We found that astrocytes stimulated with CORM-2 (CO-releasing molecule) promoted angiogenesis by increasing VEGF expression and secretion. CORM-2 also induced HO-1 (hemeoxygenase-1) expression and increased nuclear HIF-1α protein level, without altering its promoter activity and mRNA level. VEGF expression was inhibited by treatment with HIF-1α siRNA and a hemeoxygenase inhibitor, indicating that CO stimulates VEGF expression via up-regulation of HIF-1α protein level, which is partially associated with HO-1 induction. CORM-2 activated the translational regulatory proteins p70(S6k) and eIF-4E as well as phosphorylating their upstream signal mediators Akt and ERK. These translational signal events and HIF-1α protein level were suppressed by inhibitors of phosphatidylinositol 3-kinase (PI3K), MEK, and mTOR, suggesting that the PI3K/Akt/mTOR and MEK/ERK pathways are involved in a translational increase in HIF-1α. In addition, CORM-2 also increased stability of the HIF-1α protein by suppressing its ubiquitination, without altering the proline hydroxylase-dependent HIF-1α degradation pathway. CORM-2 increased HIF-1α/HSP90α interaction, which is responsible for HIF-1α stabilization, and HSP90-specific inhibitors decreased this interaction, HIF-1α protein level, and VEGF expression. Furthermore, HSP90α knockdown suppressed CORM-2-induced increases in HIF-1α and VEGF protein levels. These results suggest that CO stimulates VEGF production by increasing HIF-1α protein level via two distinct mechanisms, translational stimulation and protein stabilization of HIF-1α.
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Affiliation(s)
- Yoon Kyung Choi
- Vascular System Research Center and Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Kangwon-do 200-701, Republic of Korea
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Matsuda NM, Miller SM, Szurszewski JH. Heme-oxygenase-2 immunolabelling in pig jejunum. Acta Histochem 2010; 112:402-6. [PMID: 19232687 DOI: 10.1016/j.acthis.2009.01.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2008] [Revised: 12/03/2008] [Accepted: 01/12/2009] [Indexed: 10/21/2022]
Abstract
Heme-oxygenase-2 generates carbon monoxide in the enteric nervous system and in interstitial cells of Cajal in the canine, mouse and human jejunum. Carbon monoxide is considered a non-adrenergic and non-cholinergic inhibitory neurotransmitter and it establishes and maintains the resting membrane potential in the stomach and small intestine. The aim of this study was to determine the distribution of heme-oxygenase-2 in the enteric nervous system of the pig jejunum. Heme-oxygenase-2 immunoreactivity was found in neurons of myenteric ganglia and in nerve fibers in the circular and longitudinal muscle layers. These results suggest that carbon monoxide is produced in the enteric nervous system of the pig jejunum and might mediate inhibitory neural activity in myenteric ganglia and inhibitory neural input to smooth muscle cells in the circular and longitudinal muscle layers.
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Sha L, Farrugia G, Linden DR, Szurszewski JH. The transwall gradient across the mouse colonic circular muscle layer is carbon monoxide dependent. FASEB J 2010; 24:3840-9. [PMID: 20543114 DOI: 10.1096/fj.10-156232] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Gastric and small intestinal circular smooth muscle layers have a transwall resting membrane potential (RMP) gradient that is dependent on release of carbon monoxide (CO) from interstitial cells of Cajal (ICCs). Our aim was to determine whether a RMP gradient exists in the mouse colon and whether the gradient is CO dependent. Microelectrodes were used to record RMPs from muscle cells at different depths of the circular muscle layer from wild-type and heme oxygenase-2-knockout (HO-2-KO) mice. A transwall RMP gradient was present in wild-type mice. The CO scavenger oxyhemoglobin (20 μM) and the heme oxygenase inhibitor chromium mesoporphyrin IX (CrMP, 5 μM) abolished the transwall gradient. The gradient was absent in HO-2-KO mice. Tetrodotoxin (1 μM) caused a significant depolarization in circular smooth muscle cells throughout the circular muscle layer and abolished the transwall gradient. Removal of the submucosal neurons abolished the gradient. The majority of submucosal neurons contained HO-2 immunoreactivity (HO-2-IR), while ICCs did not. These data show for the first time that a transwall gradient exists across the circular smooth muscle layer of the mouse colon, that the gradient is due to CO, and that the source of CO is the submucosal neurons.
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Affiliation(s)
- L Sha
- Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA
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Hidaka A, Azuma YT, Nakajima H, Takeuchi T. Nitric oxide and carbon monoxide act as inhibitory neurotransmitters in the longitudinal muscle of C57BL/6J mouse distal colon. J Pharmacol Sci 2010; 112:231-41. [PMID: 20118618 DOI: 10.1254/jphs.09242fp] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
The present study was designed to identify the inhibitory neurotransmitters mediating nonadrenergic noncholinergic relaxation in the longitudinal muscle of C57/BL mouse distal colon. Relaxation induced by electrical field stimulation (EFS) was recorded isotonically in the presence of atropine and guanethidine. Cyclic guanosine-3',5'-monophosphate (cyclic GMP) content was measured by radioimmunoassay. EFS-induced relaxation was inhibited by nitro-L-arginine (L-NNA) and Sn (IV) protoporphyrin dichloride IX (SnPP-IX), a nitric oxide (NO) and carbon monoxide (CO) synthase inhibitor, respectively. A combination of both inhibitors produced an additive effect. ODQ, a soluble guanylate cyclase inhibitor, inhibited EFS-induced relaxation. NOR-1, a NO donor, and carbon monoxide-releasing molecule-2 (CORM-2), a CO donor, treatment relaxed the distal colon and increased cyclic GMP content. The effects of NOR-1 and CORM-2 were inhibited by ODQ. KT5823, a cyclic GMP-dependent protein kinase inhibitor, inhibited EFS-induced relaxation. EFS-induced relaxation in the presence of KT5823 was further inhibited by L-NNA, but not by SnPP-IX. In addition, KT5823 inhibited CORM-2-induced relaxation, but not NOR-1-induced relaxation. H89, a cyclic AMP-dependent protein kinase inhibitor, inhibited EFS-induced relaxation, and EFS-induced relaxation in the presence of H89 was further inhibited by L-NNA. These results suggested that NO and CO function as inhibitory neurotransmitters in the longitudinal muscle of C57BL mouse distal colon.
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Affiliation(s)
- Ayako Hidaka
- Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Science, Osaka Prefecture University, Rinku-Ourai Kita, Izumisano-shi 598-8531, Japan
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Abstract
Nitric oxide (NO) and carbon monoxide (CO) are well established as messenger molecules throughout the body, gasotransmitters, based on striking alterations in mice lacking the appropriate biosynthetic enzymes. Hydrogen sulfide (H(2)S) is even more chemically reactive, but until recently there was little definitive evidence for its physiologic formation. Cystathionine beta-synthase (EC 4.2.1.22), and cystathionine gamma-lyase (CSE; EC 4.4.1.1), also known as cystathionine, can generate H(2)S from cyst(e)ine. Very recent studies with mice lacking these enzymes have established that CSE is responsible for H(2)S formation in the periphery, while in the brain cystathionine beta-synthase is the biosynthetic enzyme. Endothelial-derived relaxing factor activity is reduced 80% in the mesenteric artery of mice with deletion of CSE, establishing H(2)S as a major physiologic endothelial-derived relaxing factor. H(2)S appears to signal predominantly by S-sulfhydrating cysteines in its target proteins, analogous to S-nitrosylation by NO. Whereas S-nitrosylation typically inhibits enzymes, S-sulfhydration activates them. S-nitrosylation basally affects 1-2% of its target proteins, while 10-25% of H(2)S target proteins are S-sulfhydrated. In summary, H(2)S appears to be a physiologic gasotransmitter of comparable importance to NO and carbon monoxide.
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Affiliation(s)
- Moataz M Gadalla
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2105, USA
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Stec DE, Vera T, Storm MV, McLemore GR, Ryan MJ. Blood pressure and renal blow flow responses in heme oxygenase-2 knockout mice. Am J Physiol Regul Integr Comp Physiol 2009; 297:R1822-8. [PMID: 19846746 DOI: 10.1152/ajpregu.00319.2009] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Heme oxygenase (HO) is the enzyme responsible for the breakdown of heme-generating carbon monoxide (CO) and biliverdin in this process. HO-2 is the constitutively expressed isoform in most tissues, such as the kidney and vasculature. CO generated by HO is believed to be an important vasodilator in the renal circulation along with another gas, nitric oxide (NO). To determine the importance of HO-2 in the regulation of blood pressure and renal blood flow (RBF), we treated HO-2 knockout (KO) mice chronically with either ANG II or N(G)-nitroarginine methyl ester (l-NAME). Basal blood pressures were not different between wild-type (WT), heterozygous (HET), or KO mice and averaged 113 +/- 3 vs. 115 +/- 2 vs. 116 +/- 2 mmHg. Similar increases in blood pressure to chronic ANG II as well as l-NAME treatment were observed in all groups with blood pressures increasing an average of 30 mmHg in response to ANG II and 15 mmHg in response to l-NAME. Basal RBFs were not different between the groups averaging 6.0 +/- 0.5 (n = 6) vs. 4.8 +/- 0.6 (n = 10) vs. 5.8 +/- 0.7 (n = 6) ml*min(-1)*g(-1) kidney weight in WT, HET, and KO mice. HO-2 KO and HET mice exhibited an attenuated decrease in RBF in response to acute administration of ANG II, while no differences were observed with l-NAME. Our data indicate that blood pressure and RBF responses to increased ANG II or inhibition of nitric oxide are not significantly enhanced in HO-2 KO mice.
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Affiliation(s)
- David E Stec
- Department of Physiology and Biophysics, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Mississippi 39215, USA.
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Han F, Takeda K, Ono M, Date F, Ishikawa K, Yokoyama S, Shinozawa Y, Furuyama K, Shibahara S. Hypoxemia induces expression of heme oxygenase-1 and heme oxygenase-2 proteins in the mouse myocardium. J Biochem 2009; 147:143-51. [DOI: 10.1093/jb/mvp153] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Evans JP, Kandel S, Ortiz de Montellano PR. Isocyanides inhibit human heme oxygenases at the verdoheme stage. Biochemistry 2009; 48:8920-8. [PMID: 19694439 DOI: 10.1021/bi9011258] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Heme oxygenases (HO) catalyze the oxidative cleavage of heme to generate biliverdin, CO, and free iron. In humans, heme oxygenase-1 (hHO-1) is overexpressed in tumor tissues, where it helps to protect cancer cells from anticancer agents, while HOs in fungal pathogens, such as Candida albicans, function as the primary means of iron acquisition. Thus, HO can be considered a potential therapeutic target for certain diseases. In this study, we have examined the equilibrium binding of three isocyanides, isopropyl, n-butyl, and benzyl, to the two major human HO isoforms (hHO-1 and hHO-2), Candida albicans HO (CaHmx1), and human cytochrome P450 CYP3A4 using electronic absorption spectroscopy. Isocyanides coordinate to both ferric and ferrous HO-bound heme, with tighter binding by the more hydrophobic isocyanides and 200-300-fold tighter binding to the ferrous form. Benzyl isocyanide was the strongest ligand to ferrous heme in all the enzymes. Because the dissociation constants (KD) of the ligands for ferrous heme-hHO-1 were below the limit of accuracy for equilibrium titrations, stopped-flow kinetic experiments were used to measure the binding parameters of the isocyanides to ferrous hHO-1. Steady-state activity assays showed that benzyl isocyanide was the most potent uncompetitive inhibitor with respect to heme with a KI = 0.15 microM for hHO-1. Importantly, single turnover assays revealed that the reaction was completely stopped by coordination of the isocyanide to the verdoheme intermediate rather than to the ferric heme complex. Much tighter binding of the inhibitor to the verdoheme intermediate differentiates it from inhibition of, for example, CYP3A4 and offers a possible route to more selective inhibitor design.
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Affiliation(s)
- John P Evans
- Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, California 94158-2517, USA
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Matsuda NM, Miller SM. Non-adrenergic non-cholinergic inhibition of gastrointestinal smooth muscle and its intracellular mechanism(s). Fundam Clin Pharmacol 2009; 24:261-8. [PMID: 19674117 DOI: 10.1111/j.1472-8206.2009.00761.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Relaxation of gastrointestinal smooth muscle caused by release of non-adrenergic non-cholinergic (NANC) transmitters from enteric nerves occurs in several physiologic digestive reflexes. Likely candidate NANC inhibitory agents include nitric oxide (NO), adenosine triphosphate (ATP), vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating peptide (PACAP), carbon monoxide (CO), protease-activated receptors (PARs), hydrogen sulfide (H2S), neurotensin (NT) and beta-nicotinamide adenine dinucleotide (beta-NAD). Multiple NANC transmitters work in concert, are pharmacologically coupled and are closely coordinated. Individual contribution varies regionally in the gastrointestinal tract and between species. NANC inhibition of gastrointestinal smooth muscle involves several intracellular mechanisms, including increase of cyclic guanosine monophosphate (cGMP), increase of cyclic adenosine monophosphate (cAMP) and hyperpolarization of the cell membrane via direct or indirect activation of potassium ion (K+) channels.
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Affiliation(s)
- Nilce Mitiko Matsuda
- Departamento de Cirurgia e Anatomia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil.
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