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Pagliaro P, Weber NC, Femminò S, Alloatti G, Penna C. Gasotransmitters and noble gases in cardioprotection: unraveling molecular pathways for future therapeutic strategies. Basic Res Cardiol 2024; 119:509-544. [PMID: 38878210 PMCID: PMC11319428 DOI: 10.1007/s00395-024-01061-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Revised: 05/28/2024] [Accepted: 05/29/2024] [Indexed: 08/13/2024]
Abstract
Despite recent progress, ischemic heart disease poses a persistent global challenge, driving significant morbidity and mortality. The pursuit of therapeutic solutions has led to the emergence of strategies such as ischemic preconditioning, postconditioning, and remote conditioning to shield the heart from myocardial ischemia/reperfusion injury (MIRI). These ischemic conditioning approaches, applied before, after, or at a distance from the affected organ, inspire future therapeutic strategies, including pharmacological conditioning. Gasotransmitters, comprising nitric oxide, hydrogen sulfide, sulfur dioxide, and carbon monoxide, play pivotal roles in physiological and pathological processes, exhibiting shared features such as smooth muscle relaxation, antiapoptotic effects, and anti-inflammatory properties. Despite potential risks at high concentrations, physiological levels of gasotransmitters induce vasorelaxation and promote cardioprotective effects. Noble gases, notably argon, helium, and xenon, exhibit organ-protective properties by reducing cell death, minimizing infarct size, and enhancing functional recovery in post-ischemic organs. The protective role of noble gases appears to hinge on their modulation of molecular pathways governing cell survival, leading to both pro- and antiapoptotic effects. Among noble gases, helium and xenon emerge as particularly promising in the field of cardioprotection. This overview synthesizes our current understanding of the roles played by gasotransmitters and noble gases in the context of MIRI and cardioprotection. In addition, we underscore potential future developments involving the utilization of noble gases and gasotransmitter donor molecules in advancing cardioprotective strategies.
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Affiliation(s)
- Pasquale Pagliaro
- Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, 10043, Orbassano, TO), Italy.
- National Institute for Cardiovascular Research (INRC), 40126, Bologna, Italy.
| | - Nina C Weber
- Department of Anesthesiology, Laboratory of Experimental Intensive Care and Anesthesiology-L.E.I.C.A, Amsterdam University Medical Centers, Amsterdam Cardiovascular Science (ACS), Amsterdam, The Netherlands
| | - Saveria Femminò
- Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, 10043, Orbassano, TO), Italy
| | | | - Claudia Penna
- Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, 10043, Orbassano, TO), Italy
- National Institute for Cardiovascular Research (INRC), 40126, Bologna, Italy
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Nagasaki T, Maeda H, Yanagisawa H, Nishida K, Kobayashi K, Wada N, Noguchi I, Iwakiri R, Taguchi K, Sakai H, Saruwatari J, Watanabe H, Otagiri M, Maruyama T. Carbon Monoxide-Loaded Red Blood Cell Prevents the Onset of Cisplatin-Induced Acute Kidney Injury. Antioxidants (Basel) 2023; 12:1705. [PMID: 37760008 PMCID: PMC10526101 DOI: 10.3390/antiox12091705] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 08/26/2023] [Accepted: 08/30/2023] [Indexed: 09/29/2023] Open
Abstract
Cisplatin-induced acute kidney injury (AKI) is an important factor that limits the clinical use of this drug for the treatment of malignancies. Oxidative stress and inflammation are considered to be the main causes of not only cisplatin-induced death of cancer cells but also cisplatin-induced AKI. Therefore, developing agents that exert antioxidant and anti-inflammatory effects without weakening the anti-tumor effects of cisplatin is highly desirable. Carbon monoxide (CO) has recently attracted interest due to its antioxidant, anti-inflammatory, and anti-tumor properties. Herein, we report that CO-loaded red blood cell (CO-RBC) exerts renoprotective effects on cisplatin-induced AKI. Cisplatin treatment was found to reduce cell viability in proximal tubular cells via oxidative stress and inflammation. Cisplatin-induced cytotoxicity, however, was suppressed by the CO-RBC treatment. The intraperitoneal administration of cisplatin caused an elevation in the blood urea nitrogen and serum creatinine levels. The administration of CO-RBC significantly suppressed these elevations. Furthermore, the administration of CO-RBC also reduced the deterioration of renal histology and tubular cell injury through its antioxidant and anti-inflammatory effects in cisplatin-induced AKI mice. Thus, our data suggest that CO-RBC has the potential to substantially prevent the onset of cisplatin-induced AKI, which, in turn, may improve the usefulness of cisplatin-based chemotherapy.
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Affiliation(s)
- Taisei Nagasaki
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan; (T.N.); (H.Y.); (K.N.); (K.K.); (N.W.); (I.N.); (R.I.); (H.W.)
| | - Hitoshi Maeda
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan; (T.N.); (H.Y.); (K.N.); (K.K.); (N.W.); (I.N.); (R.I.); (H.W.)
| | - Hiroki Yanagisawa
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan; (T.N.); (H.Y.); (K.N.); (K.K.); (N.W.); (I.N.); (R.I.); (H.W.)
| | - Kento Nishida
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan; (T.N.); (H.Y.); (K.N.); (K.K.); (N.W.); (I.N.); (R.I.); (H.W.)
| | - Kazuki Kobayashi
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan; (T.N.); (H.Y.); (K.N.); (K.K.); (N.W.); (I.N.); (R.I.); (H.W.)
| | - Naoki Wada
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan; (T.N.); (H.Y.); (K.N.); (K.K.); (N.W.); (I.N.); (R.I.); (H.W.)
| | - Isamu Noguchi
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan; (T.N.); (H.Y.); (K.N.); (K.K.); (N.W.); (I.N.); (R.I.); (H.W.)
| | - Ryotaro Iwakiri
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan; (T.N.); (H.Y.); (K.N.); (K.K.); (N.W.); (I.N.); (R.I.); (H.W.)
| | - Kazuaki Taguchi
- Division of Pharmacodynamics, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan;
| | - Hiromi Sakai
- Department of Chemistry, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Japan;
| | - Junji Saruwatari
- Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan;
| | - Hiroshi Watanabe
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan; (T.N.); (H.Y.); (K.N.); (K.K.); (N.W.); (I.N.); (R.I.); (H.W.)
| | - Masaki Otagiri
- Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan
- DDS Research Institute, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan
| | - Toru Maruyama
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan; (T.N.); (H.Y.); (K.N.); (K.K.); (N.W.); (I.N.); (R.I.); (H.W.)
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Arrigo E, Comità S, Pagliaro P, Penna C, Mancardi D. Clinical Applications for Gasotransmitters in the Cardiovascular System: Are We There Yet? Int J Mol Sci 2023; 24:12480. [PMID: 37569855 PMCID: PMC10419417 DOI: 10.3390/ijms241512480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/28/2023] [Accepted: 08/03/2023] [Indexed: 08/13/2023] Open
Abstract
Ischemia is the underlying mechanism in a wide variety of acute and persistent pathologies. As such, understanding the fine intracellular events occurring during (and after) the restriction of blood supply is pivotal to improving the outcomes in clinical settings. Among others, gaseous signaling molecules constitutively produced by mammalian cells (gasotransmitters) have been shown to be of potential interest for clinical treatment of ischemia/reperfusion injury. Nitric oxide (NO and its sibling, HNO), hydrogen sulfide (H2S), and carbon monoxide (CO) have long been proven to be cytoprotective in basic science experiments, and they are now awaiting confirmation with clinical trials. The aim of this work is to review the literature and the clinical trials database to address the state of development of potential therapeutic applications for NO, H2S, and CO and the clinical scenarios where they are more promising.
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Min Q, Ji X. Strategies toward Metal-Free Carbon Monoxide Prodrugs: An Update. ChemMedChem 2023; 18:e202200500. [PMID: 36251749 DOI: 10.1002/cmdc.202200500] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/14/2022] [Indexed: 01/24/2023]
Abstract
Carbon monoxide is an important gasotransmitter in mammals, with pleiotropic therapeutic potential against a wide range of human diseases. However, clinical translation of CO is severely hampered by the lack of a reliable CO delivery form. The development of metal-free CO prodrugs is the key to resolving such delivery issues. Over the past three years, some new exciting progress has been made in this field. In this review, we highlight these advances and discuss related issues.
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Affiliation(s)
- Qingqiang Min
- College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu, 215021, P. R. China
| | - Xingyue Ji
- College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu, 215021, P. R. China
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Bell NT, Payne CM, Sammut IA, Larsen DS. Mechanistic Studies of Carbon Monoxide Release from Norborn‐2‐en‐7‐one CORMs. ASIAN J ORG CHEM 2022. [DOI: 10.1002/ajoc.202200350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Affiliation(s)
- Nathan T. Bell
- University of Otago - Dunedin Campus: University of Otago Chemistry NEW ZEALAND
| | | | - Ivan A Sammut
- University of Otago Pharmacology and Toxicology NEW ZEALAND
| | - David S Larsen
- University of Otago Chemistry Union Place WestPO Box 56 Dunedin 9054 9016 Dunedin NEW ZEALAND
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Šranková M, Dvořák A, Martínek M, Šebej P, Klán P, Vítek L, Muchová L. Antiproliferative and Cytotoxic Activities of Fluorescein-A Diagnostic Angiography Dye. Int J Mol Sci 2022; 23:1504. [PMID: 35163426 PMCID: PMC8836159 DOI: 10.3390/ijms23031504] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/25/2022] [Accepted: 01/26/2022] [Indexed: 01/20/2023] Open
Abstract
Fluorescein is a fluorescent dye used as a diagnostic tool in various fields of medicine. Although fluorescein itself possesses low toxicity, after photoactivation, it releases potentially toxic molecules, such as singlet oxygen (1O2) and, as we demonstrate in this work, also carbon monoxide (CO). As both of these molecules can affect physiological processes, the main aim of this study was to explore the potential biological impacts of fluorescein photochemistry. In our in vitro study in a human hepatoblastoma HepG2 cell line, we explored the possible effects on cell viability, cellular energy metabolism, and the cell cycle. We observed markedly lowered cell viability (≈30%, 75-2400 μM) upon irradiation of intracellular fluorescein and proved that this decrease in viability was dependent on the cellular oxygen concentration. We also detected a significantly decreased concentration of Krebs cycle metabolites (lactate and citrate < 30%; 2-hydroxyglutarate and 2-oxoglutarate < 10%) as well as cell cycle arrest (decrease in the G2 phase of 18%). These observations suggest that this photochemical reaction could have important biological consequences and may account for some adverse reactions observed in fluorescein-treated patients. Additionally, the biological activities of both 1O2 and CO might have considerable therapeutic potential, particularly in the treatment of cancer.
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Affiliation(s)
- Mária Šranková
- Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital in Prague and 1st Faculty of Medicine, Charles University, Na Bojišti 3, 121 08 Praha, Czech Republic; (M.Š.); (A.D.)
| | - Aleš Dvořák
- Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital in Prague and 1st Faculty of Medicine, Charles University, Na Bojišti 3, 121 08 Praha, Czech Republic; (M.Š.); (A.D.)
| | - Marek Martínek
- RECETOX, Faculty of Science, Masaryk University, Kotlářská 2, 611 37 Brno, Czech Republic; (M.M.); (P.Š.); (P.K.)
| | - Peter Šebej
- RECETOX, Faculty of Science, Masaryk University, Kotlářská 2, 611 37 Brno, Czech Republic; (M.M.); (P.Š.); (P.K.)
| | - Petr Klán
- RECETOX, Faculty of Science, Masaryk University, Kotlářská 2, 611 37 Brno, Czech Republic; (M.M.); (P.Š.); (P.K.)
- Department of Chemistry, Faculty of Science, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic
| | - Libor Vítek
- Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital in Prague and 1st Faculty of Medicine, Charles University, Na Bojišti 3, 121 08 Praha, Czech Republic; (M.Š.); (A.D.)
- 4th Department of Internal Medicine, General University Hospital in Prague and 1st Faculty of Medicine, Charles University, U Nemocnice 2, 128 08 Praha, Czech Republic
| | - Lucie Muchová
- Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital in Prague and 1st Faculty of Medicine, Charles University, Na Bojišti 3, 121 08 Praha, Czech Republic; (M.Š.); (A.D.)
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Dias-Pedroso D, Ramalho JS, Sardão VA, Jones JG, Romão CC, Oliveira PJ, Vieira HLA. Carbon Monoxide-Neuroglobin Axis Targeting Metabolism Against Inflammation in BV-2 Microglial Cells. Mol Neurobiol 2021; 59:916-931. [PMID: 34797521 DOI: 10.1007/s12035-021-02630-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 10/29/2021] [Indexed: 01/06/2023]
Abstract
Microglia are the immune competent cell of the central nervous system (CNS), promoting brain homeostasis and regulating inflammatory response against infection and injury. Chronic or exacerbated neuroinflammation is a cause of damage in several brain pathologies. Endogenous carbon monoxide (CO), produced from the degradation of heme, is described as anti-apoptotic and anti-inflammatory in several contexts, including in the CNS. Neuroglobin (Ngb) is a haemoglobin-homologous protein, which upregulation triggers antioxidant defence and prevents neuronal apoptosis. Thus, we hypothesised a crosstalk between CO and Ngb, in particular, that the anti-neuroinflammatory role of CO in microglia depends on Ngb. A novel CO-releasing molecule (ALF826) based on molybdenum was used for delivering CO in microglial culture.BV-2 mouse microglial cell line was challenged with lipopolysaccharide (LPS) for triggering inflammation, and after 6 h ALF826 was added. CO exposure limited inflammation by decreasing inducible nitric oxide synthase (iNOS) expression and the production of nitric oxide (NO) and tumour necrosis factor-α (TNF-α), and by increasing interleukine-10 (IL-10) release. CO-induced Ngb upregulation correlated in time with CO's anti-inflammatory effect. Moreover, knocking down Ngb reversed the anti-inflammatory effect of CO, suggesting that dependents on Ngb expression. CO-induced Ngb upregulation was independent on ROS signalling, but partially dependent on the transcriptional factor SP1. Finally, microglial cell metabolism is also involved in the inflammatory response. In fact, LPS treatment decreased oxygen consumption in microglia, indicating a switch to glycolysis, which is associated with a proinflammatory. While CO treatment increased oxygen consumption, reverting LPS effect and indicating a metabolic shift into a more oxidative metabolism. Moreover, in the absence of Ngb, this phenotype was no longer observed, indicating Ngb is needed for CO's modulation of microglial metabolism. Finally, the metabolic shift induced by CO did not depend on alteration of mitochondrial population. In conclusion, neuroglobin emerges for the first time as a key player for CO signalling against exacerbated inflammation in microglia.
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Affiliation(s)
| | - José S Ramalho
- CEDOC, NOVA Medical School, Universidade Nova de Lisboa, Lisbon, Portugal
| | - Vilma A Sardão
- CNC-Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - John G Jones
- CNC-Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Carlos C Romão
- Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal
| | - Paulo J Oliveira
- CNC-Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Helena L A Vieira
- CEDOC, NOVA Medical School, Universidade Nova de Lisboa, Lisbon, Portugal. .,UCIBIO, Applied Molecular Biosciences Unit, Department of Chemistry, Faculdade de Ciências e Tecnologia, NOVA School of Science and Technology, Universidade Nova de Lisboa, Campus de Caparica, 2829-526, Caparica, Portugal. .,Associate Laboratory i4HB - Institute for Health and Bioeconomy, NOVA School of Science and Technology, Universidade Nova de Lisboa, Caparica, Portugal.
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Iqbal J, Chamberlain J, Alfaidi M, Hughes M, Alizadeh T, Casbolt H, Evans P, Mann B, Motterlini R, Francis S, Gunn J. Carbon Monoxide Releasing Molecule A1 Reduces Myocardial Damage After Acute Myocardial Infarction in a Porcine Model. J Cardiovasc Pharmacol 2021; 78:e656-e661. [PMID: 34328710 DOI: 10.1097/fjc.0000000000001067] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 05/01/2021] [Indexed: 11/25/2022]
Abstract
ABSTRACT Infarct size is a major determinant of outcomes after acute myocardial infarction (AMI). Carbon monoxide-releasing molecules (CORMs), which deliver nanomolar concentrations of carbon monoxide to tissues, have been shown to reduce infarct size in rodents. We evaluated efficacy and safety of CORM-A1 to reduce infarct size in a clinically relevant porcine model of AMI. We induced AMI in Yorkshire White pigs by inflating a coronary angioplasty balloon to completely occlude the left anterior descending artery for 60 minutes, followed by deflation of the balloon to mimic reperfusion. Fifteen minutes after balloon occlusion, animals were given an infusion of 4.27 mM CORM-A1 (n = 7) or sodium borate control (n = 6) over 60 minutes. Infarct size, cardiac biomarkers, ejection fraction, and hepatic and renal function were compared amongst the groups. Immunohistochemical analyses were performed to compare inflammation, cell proliferation, and apoptosis between the groups. CORM-A1-treated animals had significant reduction in absolute infarct area (158 ± 16 vs. 510 ± 91 mm2, P < 0.001) and infarct area corrected for area at risk (24.8% ± 2.6% vs. 45.2% ± 4.0%, P < 0.0001). Biochemical markers of myocardial injury also tended to be lower and left ventricular function tended to recover better in the CORM-A1 treated group. There was no evidence of hepatic or renal toxicity with the doses used. The cardioprotective effects of CORM-A1 were associated with a significant reduction in cell proliferation and inflammation. CORM-A1 reduces infarct size and improves left ventricular remodeling and function in a porcine model of reperfused MI by a reduction in inflammation. These potential cardioprotective effects of CORMs warrant further translational investigations.
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Affiliation(s)
- Javaid Iqbal
- Cardiology Department, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
| | - Janet Chamberlain
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
| | - Mabruka Alfaidi
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
| | - Matthew Hughes
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
| | - Tooba Alizadeh
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
| | - Helen Casbolt
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
| | - Paul Evans
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
| | - Brian Mann
- Department of Chemistry, University of Sheffield, Sheffield, United Kingdom ; and
| | | | - Sheila Francis
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
| | - Julian Gunn
- Cardiology Department, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
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Teoh JP, Li X, Simoncini T, Zhu D, Fu X. Estrogen-Mediated Gaseous Signaling Molecules in Cardiovascular Disease. Trends Endocrinol Metab 2020; 31:773-784. [PMID: 32682630 DOI: 10.1016/j.tem.2020.06.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 06/07/2020] [Accepted: 06/22/2020] [Indexed: 12/14/2022]
Abstract
Gender difference is well recognized as a key risk factor for cardiovascular disease (CVD). Estrogen, the primary female sex hormone, improves cardiovascular functions through receptor (ERα, ERβ, or G protein-coupled estrogen receptor)-initiated genomic or non-genomic mechanisms. Gaseous signaling molecules, including nitric oxide (NO), hydrogen sulfide (H2S), and carbon monoxide (CO), are important regulators of cardiovascular function. Recent studies have demonstrated that estrogen regulates the production of these signaling molecules in cardiovascular cells to exert its cardiovascular protective effects. We discuss current understanding of gaseous signaling molecules in cardiovascular disease (CVD), the underlying mechanisms through which estrogen exerts cardiovascular protective effects by regulating these molecules, and how these findings can be translated to improve the health of postmenopausal women.
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Affiliation(s)
- Jian-Peng Teoh
- Department of Gynecology and Obstetrics, Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Key Laboratory of Cardiovascular Diseases, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511518, P.R. China; Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510260, P.R. China
| | - Xiaosa Li
- Department of Gynecology and Obstetrics, Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Key Laboratory of Cardiovascular Diseases, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511518, P.R. China; Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510260, P.R. China
| | - Tommaso Simoncini
- Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development, University of Pisa, Pisa 56100, Italy
| | - Dongxing Zhu
- Department of Gynecology and Obstetrics, Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Key Laboratory of Cardiovascular Diseases, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511518, P.R. China; Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510260, P.R. China.
| | - Xiaodong Fu
- Department of Gynecology and Obstetrics, Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Key Laboratory of Cardiovascular Diseases, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511518, P.R. China; Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510260, P.R. China.
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10
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Figueiredo-Pereira C, Dias-Pedroso D, Soares NL, Vieira HLA. CO-mediated cytoprotection is dependent on cell metabolism modulation. Redox Biol 2020; 32:101470. [PMID: 32120335 PMCID: PMC7049654 DOI: 10.1016/j.redox.2020.101470] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 02/11/2020] [Accepted: 02/17/2020] [Indexed: 12/19/2022] Open
Abstract
Carbon monoxide (CO) is a gasotransmitter endogenously produced by the activity of heme oxygenase, which is a stress-response enzyme. Endogenous CO or low concentrations of exogenous CO have been described to present several cytoprotective functions: anti-apoptosis, anti-inflammatory, vasomodulation, maintenance of homeostasis, stimulation of preconditioning and modulation of cell differentiation. The present review revises and discuss how CO regulates cell metabolism and how it is involved in the distinct cytoprotective roles of CO. The first found metabolic effect of CO was its increase on cellular ATP production, and since then much data have been generated. Mitochondria are the most described and studied cellular targets of CO. Mitochondria exposure to this gasotransmitter leads several consequences: ROS generation, stimulation of mitochondrial biogenesis, increased oxidative phosphorylation or mild uncoupling effect. Likewise, CO negatively regulates glycolysis and improves pentose phosphate pathway. More recently, CO has also been disclosed as a regulating molecule for metabolic diseases, such as obesity and diabetes with promising results.
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Affiliation(s)
- Cláudia Figueiredo-Pereira
- CEDOC, Faculdade de Ciência Médicas/NOVA Medical School, Universidade Nova de Lisboa, 1169-056, Lisboa, Portugal
| | - Daniela Dias-Pedroso
- CEDOC, Faculdade de Ciência Médicas/NOVA Medical School, Universidade Nova de Lisboa, 1169-056, Lisboa, Portugal; UCIBIO, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Portugal
| | - Nuno L Soares
- CEDOC, Faculdade de Ciência Médicas/NOVA Medical School, Universidade Nova de Lisboa, 1169-056, Lisboa, Portugal; UCIBIO, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Portugal
| | - Helena L A Vieira
- CEDOC, Faculdade de Ciência Médicas/NOVA Medical School, Universidade Nova de Lisboa, 1169-056, Lisboa, Portugal; UCIBIO, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Portugal; Instituto de Biologia Experimental e Tecnológica (iBET), Apartado 12, 2781-901, Oeiras, Portugal.
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11
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Le Bourg É. Characterisation of the positive effects of mild stress on ageing and resistance to stress. Biogerontology 2020; 21:485-493. [PMID: 32189113 DOI: 10.1007/s10522-020-09870-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 03/13/2020] [Indexed: 12/17/2022]
Abstract
The positive effects of mild stress on ageing, lifespan and resistance to stress have been studied mainly in Drosophila melanogaster flies and in the nematode Caenorhabditis elegans. These studies now allow to know the effects of the strength of the mild stress and of the number of exposures, the duration of the positive effects, if mild stress is effective when applied at any age, and whether combining two or three mild stresses is more efficient than a single one. This article summarises these results.
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Affiliation(s)
- Éric Le Bourg
- Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI Toulouse), Université de Toulouse, CNRS, UPS, Toulouse, France.
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12
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Fu L, Zhang DX, Zhang LM, Song YC, Liu FH, Li Y, Wang XP, Zheng WC, Wang XD, Gui CX, Kong XJ, Kang LQ. Exogenous carbon monoxide protects against mitochondrial DNA‑induced hippocampal pyroptosis in a model of hemorrhagic shock and resuscitation. Int J Mol Med 2020; 45:1176-1186. [PMID: 32124959 PMCID: PMC7053849 DOI: 10.3892/ijmm.2020.4493] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 01/29/2020] [Indexed: 11/05/2022] Open
Abstract
Carbon monoxide‑releasing molecule‑3 (CORM‑3), which is an exogenous carbon monoxide (CO) compound, slowly releases CO under physiological conditions; this exerts neuroprotective effects against incomplete ischemia/reperfusion injury. The objective of the present study was to investigate whether the administration of CORM‑3 protects against nucleotide‑binding oligomerization domain‑like receptor pyrin domain‑3 (NLRP3) inflammasome formation and neuronal pyroptosis in the hippocampus following hemorrhagic shock and resuscitation (HSR). To establish this, an HSR model was created. Hemorrhagic shock was induced in adult male Sprague‑Dawley rats under sevoflurane anesthesia by bleeding using a heparinized syringe to maintain a mean arterial pressure of 30±5 mmHg for 60 min. Resuscitation was performed by reperfusion of the blood and, if necessary, administering sterile saline to achieve the baseline arterial pressure. Following resuscitation, CORM‑3 (4 mg/kg) was injected via the femoral vein. Neuronal pyroptosis in the hippocampus, mitochondrial morphology, mitochondrial DNA (mtDNA), brain magnetic resonance imaging, expression levels of NLRP3 and the interaction of pro‑caspase‑1 and apoptosis‑associated speck‑like protein containing a CARD domain (ASC) were examined 12 h after HSR; locomotor activity was assessed 7 days after HSR. Compared with HSR‑treated rats, CORM‑3 administration resulted in a lower level of neuronal pyroptosis in the hippocampus, improved mitochondrial morphology, a lower mtDNA level, steadier levels of metabolites, decreased expression levels of NLRP3 and pro‑caspase‑1 interacting with ASC and enhanced locomotor activity. In conclusion, treatment with CORM‑3 ameliorated impairments of locomotor and exploratory activities in a rat model of HSR. The mechanism may be associated with the inhibition of mitochondrial DNA‑induced pyroptosis via improvements in cell metabolism.
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Affiliation(s)
- Lan Fu
- Graduate School, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Dong-Xue Zhang
- Department of Gerontology, Cangzhou Central Hospital, Cangzhou, Hebei 061001, P.R. China
| | - Li-Min Zhang
- Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, Hebei 061001, P.R. China
| | - Yan-Cheng Song
- Department of Radiodiagnosis, Cangzhou Central Hospital, Cangzhou, Hebei 061001, P.R. China
| | - Feng-Hai Liu
- Department of Radiodiagnosis, Cangzhou Central Hospital, Cangzhou, Hebei 061001, P.R. China
| | - Yan Li
- Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, Hebei 061001, P.R. China
| | - Xu-Peng Wang
- Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, Hebei 061001, P.R. China
| | - Wei-Chao Zheng
- Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, Hebei 061001, P.R. China
| | - Xiao-Dong Wang
- Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, Hebei 061001, P.R. China
| | - Chun-Xiao Gui
- Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, Hebei 061001, P.R. China
| | - Xiang-Jun Kong
- Central Laboratory, Cangzhou Central Hospital, Cangzhou, Hebei 061001, P.R. China
| | - Li-Qing Kang
- Department of Radiodiagnosis, Cangzhou Central Hospital, Cangzhou, Hebei 061001, P.R. China
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13
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Yan H, Du J, Zhu S, Nie G, Zhang H, Gu Z, Zhao Y. Emerging Delivery Strategies of Carbon Monoxide for Therapeutic Applications: from CO Gas to CO Releasing Nanomaterials. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2019; 15:e1904382. [PMID: 31663244 DOI: 10.1002/smll.201904382] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 10/08/2019] [Indexed: 06/10/2023]
Abstract
Carbon monoxide (CO) therapy has emerged as a hot topic under exploration in the field of gas therapy as it shows the promise of treating various diseases. Due to the gaseous property and the high affinity for human hemoglobin, the main challenges of administrating medicinal CO are the lack of target selectivity as well as the toxic profile at relatively high concentrations. Although abundant CO releasing molecules (CORMs) with the capacity to deliver CO in biological systems have been developed, several disadvantages related to CORMs, including random diffusion, poor solubility, potential toxicity, and lack of on-demand CO release in deep tissue, still confine their practical use. Recently, the advent of versatile nanomedicine has provided a promising chance for improving the properties of naked CORMs and simultaneously realizing the therapeutic applications of CO. This review presents a brief summarization of the emerging delivery strategies of CO based on nanomaterials for therapeutic application. First, an introduction covering the therapeutic roles of CO and several frequently used CORMs is provided. Then, recent advancements in the synthesis and application of versatile CO releasing nanomaterials are elaborated. Finally, the current challenges and future directions of these important delivery strategies are proposed.
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Affiliation(s)
- Haili Yan
- College of Medical Imaging, Shanxi Medical University, Taiyuan, 030001, P. R. China
| | - Jiangfeng Du
- College of Medical Imaging, Shanxi Medical University, Taiyuan, 030001, P. R. China
| | - Shuang Zhu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Guangjun Nie
- College of Materials Science and Optoelectronic Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
- CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Chinese Academy of Sciences, Beijing, 100190, P. R. China
| | - Hui Zhang
- College of Medical Imaging, Shanxi Medical University, Taiyuan, 030001, P. R. China
| | - Zhanjun Gu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, P. R. China
- College of Materials Science and Optoelectronic Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Yuliang Zhao
- College of Materials Science and Optoelectronic Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
- CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Chinese Academy of Sciences, Beijing, 100190, P. R. China
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14
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Baehr A, Klymiuk N, Kupatt C. Evaluating Novel Targets of Ischemia Reperfusion Injury in Pig Models. Int J Mol Sci 2019; 20:E4749. [PMID: 31557793 PMCID: PMC6801853 DOI: 10.3390/ijms20194749] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 09/19/2019] [Accepted: 09/22/2019] [Indexed: 12/12/2022] Open
Abstract
Coronary heart diseases are of high relevance for health care systems in developed countries regarding patient numbers and costs. Disappointingly, the enormous effort put into the development of innovative therapies and the high numbers of clinical studies conducted are counteracted by the low numbers of therapies that become clinically effective. Evidently, pre-clinical research in its present form does not appear informative of the performance of treatments in the clinic and, even more relevant, it appears that there is hardly any consent about how to improve the predictive capacity of pre-clinical experiments. According to the steadily increasing relevance that pig models have gained in biomedical research in the recent past, we anticipate that research in pigs can be highly predictive for ischemia-reperfusion injury (IRI) therapies as well. Thus, we here describe the significance of pig models in IRI, give an overview about recent developments in evaluating such models by clinically relevant methods and present the latest insight into therapies applied to pigs under IRI.
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Affiliation(s)
- Andrea Baehr
- Klinikum Rechts der Isar, Internal Medicine I, Technical University of Munich, 81675 Munich, Germany.
- German Centre for Cardiovascular Research, Munich Heart Alliance, 80802 Munich, Germany.
| | - Nikolai Klymiuk
- Klinikum Rechts der Isar, Internal Medicine I, Technical University of Munich, 81675 Munich, Germany.
- German Centre for Cardiovascular Research, Munich Heart Alliance, 80802 Munich, Germany.
| | - Christian Kupatt
- Klinikum Rechts der Isar, Internal Medicine I, Technical University of Munich, 81675 Munich, Germany.
- German Centre for Cardiovascular Research, Munich Heart Alliance, 80802 Munich, Germany.
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15
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Braud L, Pini M, Muchova L, Manin S, Kitagishi H, Sawaki D, Czibik G, Ternacle J, Derumeaux G, Foresti R, Motterlini R. Carbon monoxide-induced metabolic switch in adipocytes improves insulin resistance in obese mice. JCI Insight 2018; 3:123485. [PMID: 30429365 DOI: 10.1172/jci.insight.123485] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 10/16/2018] [Indexed: 12/15/2022] Open
Abstract
Obesity is characterized by accumulation of adipose tissue and is one the most important risk factors in the development of insulin resistance. Carbon monoxide-releasing (CO-releasing) molecules (CO-RMs) have been reported to improve the metabolic profile of obese mice, but the underlying mechanism remains poorly defined. Here, we show that oral administration of CORM-401 to obese mice fed a high-fat diet (HFD) resulted in a significant reduction in body weight gain, accompanied by a marked improvement in glucose homeostasis. We further unmasked an action we believe to be novel, by which CO accumulates in visceral adipose tissue and uncouples mitochondrial respiration in adipocytes, ultimately leading to a concomitant switch toward glycolysis. This was accompanied by enhanced systemic and adipose tissue insulin sensitivity, as indicated by a lower blood glucose and increased Akt phosphorylation. Our findings indicate that the transient uncoupling activity of CO elicited by repetitive administration of CORM-401 is associated with lower weight gain and increased insulin sensitivity during HFD. Thus, prototypic compounds that release CO could be investigated for developing promising insulin-sensitizing agents.
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Affiliation(s)
- Laura Braud
- Inserm U955, Team 12, Créteil, France.,Faculty of Medicine, University Paris-Est, Créteil, France
| | - Maria Pini
- Faculty of Medicine, University Paris-Est, Créteil, France.,Inserm U955, Team 8, Créteil, France
| | - Lucie Muchova
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Sylvie Manin
- Inserm U955, Team 12, Créteil, France.,Faculty of Medicine, University Paris-Est, Créteil, France
| | - Hiroaki Kitagishi
- Department of Molecular Chemistry and Biochemistry, Faculty of Science and Engineering, Doshisha University, Kyotanabe, Kyoto, Japan
| | - Daigo Sawaki
- Faculty of Medicine, University Paris-Est, Créteil, France.,Inserm U955, Team 8, Créteil, France
| | - Gabor Czibik
- Faculty of Medicine, University Paris-Est, Créteil, France.,Inserm U955, Team 8, Créteil, France
| | - Julien Ternacle
- Faculty of Medicine, University Paris-Est, Créteil, France.,Inserm U955, Team 8, Créteil, France
| | - Geneviève Derumeaux
- Faculty of Medicine, University Paris-Est, Créteil, France.,Inserm U955, Team 8, Créteil, France
| | - Roberta Foresti
- Inserm U955, Team 12, Créteil, France.,Faculty of Medicine, University Paris-Est, Créteil, France
| | - Roberto Motterlini
- Inserm U955, Team 12, Créteil, France.,Faculty of Medicine, University Paris-Est, Créteil, France
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16
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Ibáñez FJ, Farías MA, Retamal-Díaz A, Espinoza JA, Kalergis AM, González PA. Pharmacological Induction of Heme Oxygenase-1 Impairs Nuclear Accumulation of Herpes Simplex Virus Capsids upon Infection. Front Microbiol 2017; 8:2108. [PMID: 29163402 PMCID: PMC5671570 DOI: 10.3389/fmicb.2017.02108] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 10/16/2017] [Indexed: 12/18/2022] Open
Abstract
Heme oxygenase-1 (HO-1) is an inducible enzyme that is expressed in response to physical and chemical stresses, such as ultraviolet radiation, hyperthermia, hypoxia, reactive oxygen species (ROS), as well as cytokines, among others. Its activity can be positively modulated by cobalt protoporphyrin (CoPP) and negatively by tin protoporphirin (SnPP). Once induced, HO-1 degrades iron-containing heme into ferrous iron (Fe2+), carbon monoxide (CO) and biliverdin. Importantly, numerous products of HO-1 are cytoprotective with anti-apoptotic, anti-oxidant, anti-inflammatory, and anti-cancer effects. The products of HO-1 also display antiviral properties against several viruses, such as the human immunodeficiency virus (HIV), influenza, hepatitis B, hepatitis C, and Ebola virus. Here, we sought to assess the effect of modulating HO-1 activity over herpes simplex virus type 2 (HSV-2) infection in epithelial cells and neurons. There are no vaccines against HSV-2 and treatment options are scarce in the immunosuppressed, in which drug-resistant variants emerge. By using HSV strains that encode structural and non-structural forms of the green fluorescent protein (GFP), we found that pharmacological induction of HO-1 activity with CoPP significantly decreases virus plaque formation and the expression of virus-encoded genes in epithelial cells as determined by flow cytometry and western blot assays. CoPP treatment did not affect virus binding to the cell surface or entry into the cytoplasm, but rather downstream events in the virus infection cycle. Furthermore, we observed that treating cells with a CO-releasing molecule (CORM-2) recapitulated some of the anti-HSV effects elicited by CoPP. Taken together, these findings indicate that HO-1 activity interferes with the replication cycle of HSV and that its antiviral effects can be recapitulated by CO.
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Affiliation(s)
- Francisco J Ibáñez
- Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Mónica A Farías
- Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Angello Retamal-Díaz
- Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Janyra A Espinoza
- Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alexis M Kalergis
- Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile.,Departamento de Endocrinología, Escuela de Medicina, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.,Institut National de la Santé et de la Recherche Médicale U1064, Nantes, France
| | - Pablo A González
- Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile
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17
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Abstract
Exposure to carbon monoxide (CO) during general anesthesia can result from volatile anesthetic degradation by carbon dioxide absorbents and rebreathing of endogenously produced CO. Although adherence to the Anesthesia Patient Safety Foundation guidelines reduces the risk of CO poisoning, patients may still experience subtoxic CO exposure during low-flow anesthesia. The consequences of such exposures are relatively unknown. In contrast to the widely recognized toxicity of high CO concentrations, the biologic activity of low concentration CO has recently been shown to be cytoprotective. As such, low-dose CO is being explored as a novel treatment for a variety of different diseases. Here, we review the concept of anesthesia-related CO exposure, identify the sources of production, detail the mechanisms of overt CO toxicity, highlight the cellular effects of low-dose CO, and discuss the potential therapeutic role for CO as part of routine anesthetic management.
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Affiliation(s)
- Richard J Levy
- From the Department of Anesthesiology, Columbia University Medical Center, New York, New York
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18
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Abstract
Part I of this review discussed the similarities between embryogenesis, mammalian adaptions to hypoxia (primarily driven by hypoxia-inducible factor-1 [HIF-1]), ischemia-reperfusion injury (and its relationship with reactive oxygen species), hibernation, diving animals, cancer, and sepsis, and it focused on the common characteristics that allow cells and organisms to survive in these states. Part II of this review describes techniques by which researchers gain insight into subcellular energetics and identify potential future tools for clinicians. In particular, P nuclear magnetic resonance to measure high-energy phosphates, serum lactate measurements, the use of near-infrared spectroscopy to measure the oxidation state of cytochrome aa3, and the ability of the protoporphyrin IX-triplet state lifetime technique to measure mitochondrial oxygen tension are discussed. In addition, this review discusses novel treatment strategies such as hyperbaric oxygen, preconditioning, exercise training, therapeutic gases, as well as inhibitors of HIF-1, HIF prolyl hydroxylase, and peroxisome proliferator-activated receptors.
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Affiliation(s)
- Robert H Thiele
- From the Department of Anesthesiology, University of Virginia, Charlottesville, Virginia
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19
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Otterbein LE, Foresti R, Motterlini R. Heme Oxygenase-1 and Carbon Monoxide in the Heart: The Balancing Act Between Danger Signaling and Pro-Survival. Circ Res 2017; 118:1940-1959. [PMID: 27283533 DOI: 10.1161/circresaha.116.306588] [Citation(s) in RCA: 159] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 05/02/2016] [Indexed: 12/22/2022]
Abstract
Understanding the processes governing the ability of the heart to repair and regenerate after injury is crucial for developing translational medical solutions. New avenues of exploration include cardiac cell therapy and cellular reprogramming targeting cell death and regeneration. An attractive possibility is the exploitation of cytoprotective genes that exist solely for self-preservation processes and serve to promote and support cell survival. Although the antioxidant and heat-shock proteins are included in this category, one enzyme that has received a great deal of attention as a master protective sentinel is heme oxygenase-1 (HO-1), the rate-limiting step in the catabolism of heme into the bioactive signaling molecules carbon monoxide, biliverdin, and iron. The remarkable cardioprotective effects ascribed to heme oxygenase-1 are best evidenced by its ability to regulate inflammatory processes, cellular signaling, and mitochondrial function ultimately mitigating myocardial tissue injury and the progression of vascular-proliferative disease. We discuss here new insights into the role of heme oxygenase-1 and heme on cardiovascular health, and importantly, how they might be leveraged to promote heart repair after injury.
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Affiliation(s)
- Leo E Otterbein
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
| | - Roberta Foresti
- Inserm, U955, Equipe 12, Créteil, 94000, France.,University Paris Est, Faculty of Medicine, Créteil, 94000, France
| | - Roberto Motterlini
- Inserm, U955, Equipe 12, Créteil, 94000, France.,University Paris Est, Faculty of Medicine, Créteil, 94000, France
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20
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Wang L, Wang A, Supplee WW, Koffler K, Cheng Y, Quezado ZMN, Levy RJ. Carbon monoxide incompletely prevents isoflurane-induced defects in murine neurodevelopment. Neurotoxicol Teratol 2017; 61:92-103. [PMID: 28131877 DOI: 10.1016/j.ntt.2017.01.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Revised: 01/17/2017] [Accepted: 01/24/2017] [Indexed: 11/29/2022]
Abstract
BACKGROUND Commonly used anesthetics have been shown to disrupt neurodevelopment in preclinical models. It has been proposed that such anesthesia-induced neurotoxicity is mediated by apoptotic neurodegeneration in the immature brain. Low dose carbon monoxide (CO) exerts cytoprotective properties and we have previously demonstrated that CO inhibits isoflurane-induced apoptosis in the developing murine brain. Here we utilized anti-apoptotic concentrations of CO to delineate the role of apoptotic neurodegeneration in anesthesia-induced neurotoxicity by assessing the effect of CO on isoflurane-induced defects in neurodevelopment. METHODS C57Bl/6 mouse pups underwent 1-hour exposure to 0ppm (air), 5ppm, or 100ppm CO in air with or without isoflurane on postnatal day 7. Cohorts were evaluated 5-7weeks post exposure with T-maze cognitive testing followed by social behavior assessment. Brain size, whole brain cellular content, and neuronal density in primary somatosensory cortex and hippocampal CA3 region were measured as secondary outcomes 1-week or 5-7weeks post exposure along with 7-day old, unexposed controls. RESULTS Isoflurane impaired memory acquisition and resulted in abnormal social behavior. Low concentration CO abrogated anesthetic-induced defects in memory acquisition, however, it also resulted in impaired spatial reference memory and social behavior abnormalities. Changes in brain size, cellular content, and neuronal density over time related to the age of the animal and were unaffected by either isoflurane or CO. CONCLUSIONS Anti-apoptotic concentrations of CO incompletely prevented isoflurane-induced defects in neurodevelopment, lacked concentration-dependent effects, and only provided protection in certain domains suggesting that anesthesia-related neurotoxicity is not solely mediated by activation of the mitochondrial apoptosis pathway.
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Affiliation(s)
- Li Wang
- The Sheikh Zayed Institute for Pediatric Surgical Innovation, Division of Pain Medicine, Children's National Health System, Children's Research Institute, The George Washington University School of Medicine and Health Sciences, United States
| | - Aili Wang
- Department of Anesthesiology, Columbia University Medical Center, United States
| | | | - Kayla Koffler
- Department of Anesthesiology, Columbia University Medical Center, United States
| | - Ying Cheng
- Center for Genetic Medicine Research, Children's National Health System, Children's Research Institute, The George Washington University School of Medicine and Health Sciences, United States
| | - Zenaide M N Quezado
- The Sheikh Zayed Institute for Pediatric Surgical Innovation, Division of Pain Medicine, Children's National Health System, Children's Research Institute, The George Washington University School of Medicine and Health Sciences, United States
| | - Richard J Levy
- Department of Anesthesiology, Columbia University Medical Center, United States.
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21
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Levy RJ. Carbon monoxide and anesthesia-induced neurotoxicity. Neurotoxicol Teratol 2016; 60:50-58. [PMID: 27616667 DOI: 10.1016/j.ntt.2016.09.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2016] [Revised: 08/10/2016] [Accepted: 09/06/2016] [Indexed: 10/21/2022]
Abstract
The majority of commonly used anesthetic agents induce widespread neuronal degeneration in the developing mammalian brain. Downstream, the process appears to involve activation of the oxidative stress-associated mitochondrial apoptosis pathway. Targeting this pathway could result in prevention of anesthetic toxicity in the immature brain. Carbon monoxide (CO) is a gas that exerts biological activity in the developing brain and low dose exposures have the potential to provide neuroprotection. In recent work, low concentration CO exposures limited isoflurane-induced neuronal apoptosis in a dose-dependent manner in newborn mice and modulated oxidative stress within forebrain mitochondria. Because infants and children are routinely exposed to low levels of CO during low-flow general endotracheal anesthesia, such anti-oxidant and pro-survival cellular effects are clinically relevant. Here we provide an overview of anesthesia-related CO exposure, discuss the biological activity of low concentration CO, detail the effects of CO in the brain during development, and provide evidence for CO-mediated inhibition of anesthesia-induced neurotoxicity.
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Affiliation(s)
- Richard J Levy
- Department of Anesthesiology, Columbia University Medical Center, United States.
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22
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R Oliveira S, Queiroga CSF, Vieira HLA. Mitochondria and carbon monoxide: cytoprotection and control of cell metabolism - a role for Ca(2+) ? J Physiol 2016; 594:4131-8. [PMID: 26377343 PMCID: PMC4967755 DOI: 10.1113/jp270955] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 09/13/2015] [Indexed: 12/20/2022] Open
Abstract
Carbon monoxide (CO) is an endogenously produced gasotransmitter with important biological functions: anti-inflammation, anti-apoptosis, vasomodulation and cell metabolism modulation. The most recognized cellular target for CO is the mitochondria. Physiological concentrations of CO generate mitochondrial reactive oxygen species (ROS), which are signalling molecules for CO-induced pathways. Indeed, small amounts of ROS promote cytoprotection by a preconditioning effect. Furthermore, CO prevents cell death by limiting mitochondrial membrane permeabilization, which inhibits the release of pro-apoptotic factors into the cytosol; both events are ROS dependent. CO also increases the ability of mitochondria to take up Ca(2+) . Mitochondrial metabolism is modulated by CO, namely by increasing TCA cycle rate, oxidative phosphorylation and mitochondrial biogenesis, which, in turn, increases ATP production. CO's modulation of metabolism might be important for cellular response to diseases, namely cancer and ischaemic diseases. Finally, another cytoprotective role of CO involves the control of Ca(2+) channels. By limiting the activity of T-type and L-type Ca(2+) channels, CO prevents excitotoxicity-induced cell death and modulates cell proliferation. Several questions concerning Ca(2+) signalling, mitochondria and CO can be asked, for instance whether CO modulation of cell metabolism would be dependent on the mitochondrial Ca(2+) uptake capacity, since small amounts of Ca(2+) can increase mitochondrial metabolism. Whether CO controls Ca(2+) communication between mitochondria and endoplasmic reticulum is another open field of research. In summary, CO emerges as a key gasotransmitter in the control of several cellular functions of mitochondria: metabolism, cell death and Ca(2+) signalling.
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Affiliation(s)
- Sara R Oliveira
- CEDOC, NOVA Medical School, Universidade Nova de Lisboa, 1169-056, Lisboa, Portugal
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal
| | - Cláudia S F Queiroga
- CEDOC, NOVA Medical School, Universidade Nova de Lisboa, 1169-056, Lisboa, Portugal
| | - Helena L A Vieira
- CEDOC, NOVA Medical School, Universidade Nova de Lisboa, 1169-056, Lisboa, Portugal
- Instituto de Biologia Experimental e Tecnológica (iBET), Apartado 12, 2781-901 Oeiras, Portugal
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Recipient Hyperbilirubinemia May Reduce Ischemia-Reperfusion Injury but Fails to Improve Outcome in Clinical Liver Transplantation. Gastroenterol Res Pract 2016; 2016:6964856. [PMID: 27313607 PMCID: PMC4893452 DOI: 10.1155/2016/6964856] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 04/24/2016] [Indexed: 02/07/2023] Open
Abstract
Background. Exogenous bilirubin may reduce experimental ischemia-reperfusion injury (IRI) due to its antioxidant properties. We studied if early graft exposure to high bilirubin levels in the recipient affects the early IRI and outcomes after liver transplantation (LTx). Methods. In 427 LTx patients, the AUROC curve based on bilirubin and AST at day 1 identified a cutoff of 2.04 mg/dL for the recipient pretransplant bilirubin. Recipients were grouped as having low (group L, n = 152) or high (group H, n = 275) bilirubin. Both groups had similar donor-related variables (age, preservation time, donor BMI > 28, and donor risk index (DRI)). Results. Alanine (ALT) and aspartate (AST) aminotransferase levels were higher in group L at day 1; ALT levels remained higher at day 2 in group L. LTx from high risk donors (DRI > 2) revealed a trend towards lower transaminases during the first two days after transplantation in group H. One month and 1-year patient survival were similar in groups L and H. High preoperative bilirubin did not affect the risk for early graft dysfunction (EGD), death, or graft loss during the first year after transplantation nor the incidence of acute rejection. LTx using donors with DRI > 2 resulted in similar rates of EGD in both groups. Conclusion. Increased bilirubin appears to reduce the early IRI after LTx yet this improvement was insufficient to improve the clinical outcome.
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Ji X, Damera K, Zheng Y, Yu B, Otterbein LE, Wang B. Toward Carbon Monoxide-Based Therapeutics: Critical Drug Delivery and Developability Issues. J Pharm Sci 2016; 105:406-416. [PMID: 26869408 PMCID: PMC4755352 DOI: 10.1016/j.xphs.2015.10.018] [Citation(s) in RCA: 132] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Revised: 10/17/2015] [Accepted: 10/19/2015] [Indexed: 12/20/2022]
Abstract
Carbon monoxide (CO) is an intrinsic signaling molecule with importance on par with that of nitric oxide. During the past decade, pharmacologic studies have amply demonstrated the therapeutic potential of carbon monoxide. However, such studies were mostly based on CO inhalation and metal-based CO-releasing molecules. The field is now at the stage that a major effort is needed to develop pharmaceutically acceptable forms of CO for delivery via various routes such as oral, injection, infusion, or topical applications. This review examines the state of the art, discusses the existing hurdles to overcome, and proposes developmental strategies necessary to address remaining drug delivery issues.
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Affiliation(s)
- Xingyue Ji
- Department of Chemistry and the Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia, 30303
| | - Krishna Damera
- Department of Chemistry and the Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia, 30303
| | - Yueqin Zheng
- Department of Chemistry and the Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia, 30303
| | - Bingchen Yu
- Department of Chemistry and the Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia, 30303
| | - Leo E Otterbein
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, 02215
| | - Binghe Wang
- Department of Chemistry and the Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia, 30303.
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Le Bourg É. Life-time protection against severe heat stress by exposing young Drosophila melanogaster flies to a mild cold stress. Biogerontology 2015; 17:409-15. [PMID: 26704618 DOI: 10.1007/s10522-015-9629-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 12/18/2015] [Indexed: 10/22/2022]
Abstract
Previous studies in the laboratory of the author have shown that subjecting flies to a mild stress (e.g. a cold stress) during the first 2 weeks of adult life can increase lifespan and resistance to severe stresses (e.g. heat and fungal infection) at 6 weeks of age (ca the mean lifespan at 25 °C). This result could either show that a mild stress protects flies against severe stress for the entire life or for a duration of 4 weeks. To clarify the issue, young flies living at 25 °C were pretreated with a cold stress and thereafter transferred at 19 or 22 °C, which increases lifespan. The mild cold stress protected these flies from heat at ages when flies kept at 25 °C are dead, i.e. at 10 weeks of age or 8 weeks after the end of cold stress. Thus, a mild stress protects flies for life, even if the duration of life is increased. Because temperature can strongly vary from day to day in the wild, and lifespan of flies too, it would be a selective advantage if the ability to survive a strong stress after having been subjected to a mild stress would be maintained not only for a few days but for life, whatever its duration could be. If flies would be subjected to a mild stress when living at 25 °C, a temperature change from e.g. 25 to 22 °C would increase their lifespan and they could survive a strong stress at an age when flies kept at 25 °C are dead.
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Affiliation(s)
- Éric Le Bourg
- Centre de Recherches sur la Cognition Animale, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, Toulouse, France.
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Cinti A, De Giorgi M, Chisci E, Arena C, Galimberti G, Farina L, Bugarin C, Rivolta I, Gaipa G, Smolenski RT, Cerrito MG, Lavitrano M, Giovannoni R. Simultaneous Overexpression of Functional Human HO-1, E5NT and ENTPD1 Protects Murine Fibroblasts against TNF-α-Induced Injury In Vitro. PLoS One 2015; 10:e0141933. [PMID: 26513260 PMCID: PMC4626094 DOI: 10.1371/journal.pone.0141933] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Accepted: 10/14/2015] [Indexed: 12/17/2022] Open
Abstract
Several biomedical applications, such as xenotransplantation, require multiple genes simultaneously expressed in eukaryotic cells. Advances in genetic engineering technologies have led to the development of efficient polycistronic vectors based on the use of the 2A self-processing oligopeptide. The aim of this work was to evaluate the protective effects of the simultaneous expression of a novel combination of anti-inflammatory human genes, ENTPD1, E5NT and HO-1, in eukaryotic cells. We produced an F2A system-based multicistronic construct to express three human proteins in NIH3T3 cells exposed to an inflammatory stimulus represented by tumor necrosis factor alpha (TNF-α), a pro-inflammatory cytokine which plays an important role during inflammation, cell proliferation, differentiation and apoptosis and in the inflammatory response during ischemia/reperfusion injury in several organ transplantation settings. The protective effects against TNF-α-induced cytotoxicity and cell death, mediated by HO-1, ENTPD1 and E5NT genes were better observed in cells expressing the combination of genes as compared to cells expressing each single gene and the effect was further improved by administrating enzymatic substrates of the human genes to the cells. Moreover, a gene expression analyses demonstrated that the expression of the three genes has a role in modulating key regulators of TNF-α signalling pathway, namely Nemo and Tnfaip3, that promoted pro-survival phenotype in TNF-α injured cells. These results could provide new insights in the research of protective mechanisms in transplantation settings.
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Affiliation(s)
- Alessandro Cinti
- Department of Surgery and Translational Medicine, University of Milano-Bicocca, Monza, Italy
| | - Marco De Giorgi
- Department of Surgery and Translational Medicine, University of Milano-Bicocca, Monza, Italy
- Medical University of Gdansk, Gdansk, Poland
| | - Elisa Chisci
- Department of Surgery and Translational Medicine, University of Milano-Bicocca, Monza, Italy
| | - Claudia Arena
- Department of Surgery and Translational Medicine, University of Milano-Bicocca, Monza, Italy
| | - Gloria Galimberti
- Department of Surgery and Translational Medicine, University of Milano-Bicocca, Monza, Italy
| | - Laura Farina
- Department of Surgery and Translational Medicine, University of Milano-Bicocca, Monza, Italy
| | - Cristina Bugarin
- M. Tettamanti Research Center, Pediatric Clinic, University of Milano Bicocca, Monza, Italy
| | - Ilaria Rivolta
- Department of Health Sciences, University of Milano-Bicocca, Monza, Italy
| | - Giuseppe Gaipa
- M. Tettamanti Research Center, Pediatric Clinic, University of Milano Bicocca, Monza, Italy
| | - Ryszard Tom Smolenski
- Department of Surgery and Translational Medicine, University of Milano-Bicocca, Monza, Italy
- Medical University of Gdansk, Gdansk, Poland
| | - Maria Grazia Cerrito
- Department of Surgery and Translational Medicine, University of Milano-Bicocca, Monza, Italy
| | - Marialuisa Lavitrano
- Department of Surgery and Translational Medicine, University of Milano-Bicocca, Monza, Italy
| | - Roberto Giovannoni
- Department of Surgery and Translational Medicine, University of Milano-Bicocca, Monza, Italy
- * E-mail:
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Fletcher ME, Boshier PR, Wakabayashi K, Keun HC, Smolenski RT, Kirkham PA, Adcock IM, Barton PJ, Takata M, Marczin N. Influence of glutathione-S-transferase (GST) inhibition on lung epithelial cell injury: role of oxidative stress and metabolism. Am J Physiol Lung Cell Mol Physiol 2015; 308:L1274-85. [DOI: 10.1152/ajplung.00220.2014] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Accepted: 04/01/2015] [Indexed: 11/22/2022] Open
Abstract
Oxidant-mediated tissue injury is key to the pathogenesis of acute lung injury. Glutathione- S-transferases (GSTs) are important detoxifying enzymes that catalyze the conjugation of glutathione with toxic oxidant compounds and are associated with acute and chronic inflammatory lung diseases. We hypothesized that attenuation of cellular GST enzymes would augment intracellular oxidative and metabolic stress and induce lung cell injury. Treatment of murine lung epithelial cells with GST inhibitors, ethacrynic acid (EA), and caffeic acid compromised lung epithelial cell viability in a concentration-dependent manner. These inhibitors also potentiated cell injury induced by hydrogen peroxide (H2O2), tert-butyl-hydroperoxide, and hypoxia and reoxygenation (HR). SiRNA-mediated attenuation of GST-π but not GST-μ expression reduced cell viability and significantly enhanced stress (H2O2/HR)-induced injury. GST inhibitors also induced intracellular oxidative stress (measured by dihydrorhodamine 123 and dichlorofluorescein fluorescence), caused alterations in overall intracellular redox status (as evidenced by NAD+/NADH ratios), and increased protein carbonyl formation. Furthermore, the antioxidant N-acetylcysteine completely prevented EA-induced oxidative stress and cytotoxicity. Whereas EA had no effect on mitochondrial energetics, it significantly altered cellular metabolic profile. To explore the physiological impact of these cellular events, we used an ex vivo mouse-isolated perfused lung model. Supplementation of perfusate with EA markedly affected lung mechanics and significantly increased lung permeability. The results of our combined genetic, pharmacological, and metabolic studies on multiple platforms suggest the importance of GST enzymes, specifically GST-π, in the cellular and whole lung response to acute oxidative and metabolic stress. These may have important clinical implications.
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Affiliation(s)
- Marianne E. Fletcher
- Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, United Kingdom
| | - Piers R. Boshier
- Biosurgery and Surgical Technology, Imperial College London, London, United Kingdom
| | - Kenji Wakabayashi
- Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, United Kingdom
| | - Hector C. Keun
- Biomolecular Medicine, Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Ryszard T. Smolenski
- Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland
- Department of Surgery and Translational Medicine, University of Milano-Bicocca, Milano, Italy
| | - Paul A. Kirkham
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
- Department of Biomedical Sciences, University of Wolverhampton, Wolverhampton, United Kingdom
| | - Ian M. Adcock
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Paul J. Barton
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Masao Takata
- Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, United Kingdom
| | - Nandor Marczin
- Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, United Kingdom
- Department of Anaesthetics, Royal Brompton and Harefield NHS Foundation Trust, Harefield Hospital, Harefield, Middlesex, United Kingdom
- Department of Anaesthesia and Intensive Therapy, Semmelweis University, Budapest, Hungary
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Roderique JD, Josef CS, Feldman MJ, Spiess BD. A modern literature review of carbon monoxide poisoning theories, therapies, and potential targets for therapy advancement. Toxicology 2015; 334:45-58. [PMID: 25997893 DOI: 10.1016/j.tox.2015.05.004] [Citation(s) in RCA: 102] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2015] [Revised: 05/01/2015] [Accepted: 05/12/2015] [Indexed: 01/03/2023]
Abstract
The first descriptions of carbon monoxide (CO) and its toxic nature appeared in the literature over 100 years ago in separate publications by Drs. Douglas and Haldane. Both men ascribed the deleterious effects of this newly discovered gas to its strong interaction with hemoglobin. Since then the adverse sequelae of CO poisoning has been almost universally attributed to hypoxic injury secondary to CO occupation of oxygen binding sites on hemoglobin. Despite a mounting body of literature suggesting other mechanisms of injury, this pathophysiology and its associated oxygen centric therapies persists. This review attempts to elucidate the remarkably complex nature of CO as a gasotransmitter. While CO's affinity for hemoglobin remains undisputed, new research suggests that its role in nitric oxide release, reactive oxygen species formation, and its direct action on ion channels is much more significant. In the course of understanding the multifaceted character of this simple molecule it becomes apparent that current oxygen based therapies meant to displace CO from hemoglobin may be insufficient and possibly harmful. Approaching CO as a complex gasotransmitter will help guide understanding of the complex and poorly understood sequelae and illuminate potentials for new treatment modalities.
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Affiliation(s)
- Joseph D Roderique
- Department of Anesthesiology, VCU School of Medicine Sanger Hall, Rm B1-016, 1101 East Marshall Street, P.O. Box 980695, Richmond, VA 23298, United States
| | - Christopher S Josef
- Department of Anesthesiology, VCU School of Medicine Sanger Hall, Rm B1-016, 1101 East Marshall Street, P.O. Box 980695, Richmond, VA 23298, United States.
| | - Michael J Feldman
- Department of Plastic and Reconstructive Surgery, Critical Care Hospital 8th floor, 1213 East Clay St, Richmond, VA 23298, United States
| | - Bruce D Spiess
- Department of Anesthesiology, VCU School of Medicine Sanger Hall, Rm B1-016, 1101 East Marshall Street, P.O. Box 980695, Richmond, VA 23298, United States
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Le Bourg É. Fasting and other mild stresses with hormetic effects in Drosophila melanogaster can additively increase resistance to cold. Biogerontology 2015; 16:517-27. [DOI: 10.1007/s10522-015-9574-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Accepted: 04/06/2015] [Indexed: 11/29/2022]
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Affiliation(s)
- Éric Le Bourg
- Université Paul-Sabatier, Centre de Recherche sur la Cognition Animale, UMR CNRS 5169, 118 route de Narbonne, 31062 Toulouse cedex 9, France
| | - Suresh I S Rattan
- Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, DK8000 Aarhus - C, Denmark
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31
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Bourg ÉL, Rattan SIS. Hormesis and Trade-Offs: A Comment. Dose Response 2014. [DOI: 10.2203/dose-response.14-054.le_bourg] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
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Czibik G, Derumeaux G, Sawaki D, Valen G, Motterlini R. Heme oxygenase-1: an emerging therapeutic target to curb cardiac pathology. Basic Res Cardiol 2014; 109:450. [PMID: 25344086 DOI: 10.1007/s00395-014-0450-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Revised: 10/05/2014] [Accepted: 10/17/2014] [Indexed: 12/18/2022]
Abstract
Activation of heme oxygenase-1 (HO-1), a heme-degrading enzyme responsive to a wide range of cellular stress, is traditionally considered to convey adaptive responses to oxidative stress, inflammation and vasoconstriction. These diversified effects are achieved through the degradation of heme to carbon monoxide (CO), biliverdin (which is rapidly converted to bilirubin by biliverdin reductase) and ferric iron. Recent findings have added antiproliferative and angiogenic effects to the list of HO-1/CO actions. HO-1 along with its reaction products bilirubin and CO are protective against ischemia-induced injury (myocardial infarction, ischemia-reperfusion (IR)-injury and post-infarct structural remodelling). Moreover, HO-1, and CO in particular, possess acute antihypertensive effects. As opposed to these curative potentials, the long-believed protective effect of HO-1 in cardiac remodelling in response to pressure overload and type 2 diabetes mellitus (DM) has been questioned by recent work. These challenges, coupled with emerging regulatory mechanisms, motivate further in-depth studies to help understand untapped layers of HO-1 regulation and action. The outcomes of these efforts may shed new light on critical mechanisms that could be used to harness the protective potential of this enzyme for the therapeutic benefit of patients suffering from such highly prevalent cardiovascular disorders.
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Affiliation(s)
- Gabor Czibik
- INSERM U955, Equipe 8, Faculty of Medicine, DHU A-TVB, Hôpital Henri Mondor, APHP, Creteil, University of Paris-Est, 3rd Floor, room 3006, Paris, France,
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Abstract
SIGNIFICANCE Heme oxygenase enzymes, which exist as constitutive (HO-2) and inducible (HO-1) isoforms, degrade heme to carbon monoxide (CO) and the bile pigment biliverdin. In the last two decades, substantial scientific evidence has been collected on the function of HO-1 in cell homeostasis, emphasizing these two important features: (i) HO-1 is a fundamental "sensor" of cellular stress and directly contributes toward limiting or preventing tissue damage; (ii) the products of HO-1 activity dynamically participate in cellular adaptation to stress and are inherently involved in the mechanisms of defence. RECENT ADVANCES On the basis of its promising cytoprotective features, scientists have pursued the targeting of HO-1 as an attractive cellular pathway for drug discovery. Three different pharmacological approaches are currently being investigated in relation to HO-1, namely the use of CO gas, the development of CO-releasing molecules (CO-RMs), and small molecules possessing the ability to up-regulate HO-1 in cells and tissues. CRITICAL ISSUE: Studies on the regulation and amplification of the HO-1/CO pathway by selective pharmacological approaches may lead to the discovery of novel drugs for the treatment of a variety of diseases. FUTURE DIRECTIONS In this review, we will discuss in detail the importance of pharmacologically manipulating the HO-1 pathway and its products for conferring protection against a variety of conditions that are characterized by oxidative stress and inflammation. We will also evaluate each of the strategic approaches being developed by considering their intrinsic advantages and disadvantages, which may have implications for their use as therapeutics in specific pathological conditions.
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Biliverdin protects against liver ischemia reperfusion injury in swine. PLoS One 2013; 8:e69972. [PMID: 23922878 PMCID: PMC3726748 DOI: 10.1371/journal.pone.0069972] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Accepted: 06/12/2013] [Indexed: 01/21/2023] Open
Abstract
Ischemia reperfusion injury (IRI) in organ transplantation remains a serious and unsolved problem. Organs that undergo significant damage during IRI, function less well immediately after reperfusion and tend to have more problems at later times when rejection can occur. Biliverdin has emerged as an agent that potently suppress IRI in rodent models. Since the use of biliverdin is being developed as a potential therapeutic modality for humans, we tested the efficacy for its effects on IRI of the liver in swine, an accepted and relevant pre-clinical animal model. Administration of biliverdin resulted in rapid appearance of bilirubin in the serum and significantly suppressed IRI-induced liver dysfunction as measured by multiple parameters including urea and ammonia clearance, neutrophil infiltration and tissue histopathology including hepatocyte cell death. Taken together, our findings, in a large animal model, provide strong support for the continued evaluation of biliverdin as a potential therapeutic in the clinical setting of transplantation of the liver and perhaps other organs.
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Liao YF, Zhu W, Li DP, Zhu X. Heme oxygenase-1 and gut ischemia/reperfusion injury: A short review. World J Gastroenterol 2013; 19:3555-3561. [PMID: 23801856 PMCID: PMC3691047 DOI: 10.3748/wjg.v19.i23.3555] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2013] [Revised: 01/19/2013] [Accepted: 04/11/2013] [Indexed: 02/06/2023] Open
Abstract
Ischemia/reperfusion (I/R) injury of the gut is a significant problem in a variety of clinical settings and is associated with a high morbidity and mortality. Although the mechanisms involved in the pathogenesis of gut I/R injury have not been fully elucidated, it is generally believed that oxidative stress with subsequent inflammatory injury plays an important role. Heme oxygenase (HO) is the rate-limiting enzyme in the catabolism of heme, followed by production of CO, biliverdin, and free iron. The HO system is believed to confer cytoprotection by inhibiting inflammation, oxidation, and apoptosis, and maintaining microcirculation. HO-1, an inducible form of HO, serves a vital metabolic function as the rate-limiting step in the heme degradation pathway, and affords protection in models of intestinal I/R injury. HO-1 system is an important player in intestinal I/R injury condition, and may offer new targets for the management of this condition.
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Soni HM, Jain MR, Mehta AA. Mechanism(s) Involved in Carbon Monoxide-releasing Molecule-2-mediated Cardioprotection During Ischaemia-reperfusion Injury in Isolated Rat Heart. Indian J Pharm Sci 2013; 74:281-91. [PMID: 23626383 PMCID: PMC3630723 DOI: 10.4103/0250-474x.107047] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2011] [Revised: 07/18/2012] [Accepted: 07/20/2012] [Indexed: 12/01/2022] Open
Abstract
The purpose of the present study was to determine the mechanism(s) involved in carbon monoxide-releasing molecule-2, carbon monoxide-releasing molecule-2-induced cardioprotection. We used the transition metal carbonyl compound carbon monoxide-releasing molecule-2 that can act as carbon monoxide donor in cardiac ischaemia-reperfusion injury model using isolated rat heart preparation. Langendorff's perfused rat hearts when treated with carbon monoxide-releasing molecule-2 (50 μM) for 10 min before global ischaemia exhibited significant reduction in postischaemic levels of myocardial injury markers, creatine kinase and lactate dehydrogenase in coronary effluent. Similarly, pretreatment with carbon monoxide-releasing molecule-2 showed significantly improved postischaemic recovery of heart rate, coronary flow rate, cardiodynamic parameters and reduced infarct size as compared to vehicle control hearts. Perfusion with p38 mitogen-activated protein kinase inhibitor, SB203580, a specific inhibitor of α and β isoform, before and concomitantly with carbon monoxide-releasing molecule-2 treatment abolished carbon monoxide-releasing molecule-2-induced cardioprotection. However, p38 mitogen-activated protein kinase alpha inhibitor, SCIO-469, was unable to inhibit the cardioprotective effect of carbon monoxide-releasing molecule-2. Furthermore, protective effect of carbon monoxide-releasing molecule-2 was significantly inhibited by the protein kinase C inhibitor, chelerythrine, when added before and concomitantly with carbon monoxide-releasing molecule-2. It was also observed that, perfusion with phosphatidylinositol 3-kinase inhibitor, wortmannin, before and concomitantly with carbon monoxide-releasing molecule-2 was not able to inhibit carbon monoxide-releasing molecule-2-induced cardioprotection. Interestingly, we observed that wortmannin perfusion before ischaemia and continued till reperfusion significantly inhibited carbon monoxide-releasing molecule-2-mediated cardioprotection. Our findings suggest that the carbon monoxide-releasing molecule-2 treatment may activate the p38 mitogen-activated protein kinase β and protein kinase C pathways before ischaemia and phosphatidylinositol 3-kinase pathway during reperfusion which may be responsible for the carbon monoxide-releasing molecule-2-mediated cardioprotective effect.
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Affiliation(s)
- H M Soni
- Department of Pharmacology, L.M. College of Pharmacy, Navarangpura, Ahmedabad-380 009, India ; Zydus Research Centre, Sarkhej-Bavla, NH 8A Moraiya, Ahmedabad-382 210, India
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Reboul C, Thireau J, Meyer G, André L, Obert P, Cazorla O, Richard S. Carbon monoxide exposure in the urban environment: An insidious foe for the heart? Respir Physiol Neurobiol 2012; 184:204-12. [DOI: 10.1016/j.resp.2012.06.010] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2012] [Revised: 06/05/2012] [Accepted: 06/06/2012] [Indexed: 12/20/2022]
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Inhalation of carbon monoxide reduces skeletal muscle injury after hind limb ischemia-reperfusion injury in mice. Am J Surg 2012; 203:488-95. [PMID: 22450026 DOI: 10.1016/j.amjsurg.2011.05.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2010] [Revised: 05/24/2011] [Accepted: 05/24/2011] [Indexed: 12/15/2022]
Abstract
BACKGROUND The purpose of this study was to determine if inhaled carbon monoxide (CO) can ameliorate skeletal muscle injury, modulate endogenous heme oxygenase-1 expression, and improve indexes of tissue integrity and inflammation after hind limb ischemia reperfusion. METHODS C57BL6 mice inhaling CO (250 ppm) or room air were subjected to 1.5 hours of ischemia followed by limb reperfusion for either 3 or 6 hours (total treatment time, 4.5 or 7.5 h). After the initial period of reperfusion, all mice breathed only room air until 24 hours after the onset of ischemia. Mice were killed at either the end of CO treatment or at 24 hours' reperfusion. Skeletal muscle was subjected to histologic and biochemical analysis. RESULTS CO treatment for 7.5 hours protected skeletal muscle from histologic and structural evidence of skeletal muscle injury. Serum and tissue cytokines were reduced significantly (P < .05) in mice treated with CO for 7.5 hours. Tubulin, heme oxygenase, and adenosine triphosphate levels were higher in CO-treated mice. CONCLUSIONS Inhaled CO protected muscle from structural injury and energy depletion after ischemia reperfusion.
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Abstract
Mitochondria present two key roles on cellular functioning: (i) cell metabolism, being the main cellular source of energy and (ii) modulation of cell death, by mitochondrial membrane permeabilization. Carbon monoxide (CO) is an endogenously produced gaseoustransmitter, which presents several biological functions and is involved in maintaining cell homeostasis and cytoprotection. Herein, mitochondrion is approached as the main cellular target of carbon monoxide (CO). In this paper, two main perspectives concerning CO modulation of mitochondrial functioning are evaluated. First, the role of CO on cellular metabolism, in particular oxidative phosphorylation, is discussed, namely, on: cytochrome c oxidase activity, mitochondrial respiration, oxygen consumption, mitochondrial biogenesis, and general cellular energetic status. Second, the mitochondrial pathways involved in cell death inhibition by CO are assessed, in particular the control of mitochondrial membrane permeabilization.
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Gullotta F, di Masi A, Ascenzi P. Carbon monoxide: an unusual drug. IUBMB Life 2012; 64:378-86. [PMID: 22431507 DOI: 10.1002/iub.1015] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2011] [Accepted: 02/03/2012] [Indexed: 12/22/2022]
Abstract
The highly toxic gas carbon monoxide (CO) displays many physiological roles in several organs and tissues. Although many diseases, including cancer, hematological diseases, hypertension, heart failure, inflammation, sepsis, neurodegeneration, and sleep disorders, have been linked to abnormal endogenous CO metabolism and functions, CO administration has therapeutic potential in inflammation, sepsis, lung injury, cardiovascular diseases, transplantation, and cancer. Here, insights into the CO-based therapy, characterized by the induction or gene transfer of heme oxygenase-1 and either gas or CO-releasing molecule administration, are reviewed.
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Affiliation(s)
- Francesca Gullotta
- Department of Biology and Interdepartmental Laboratory for Electron Microscopy, University Roma Tre, Roma, Italy
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Exogenous carbon monoxide does not affect cell membrane energy availability assessed by sarcolemmal calcium fluxes during myocardial ischaemia-reperfusion in the pig. Eur J Anaesthesiol 2011; 28:356-62. [PMID: 20811288 DOI: 10.1097/eja.0b013e32833eab96] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Carbon monoxide is thought to be cytoprotective and may hold therapeutic promise for mitigating ischaemic injury. The purpose of this study was to test low-dose carbon monoxide for protective effects in a porcine model of acute myocardial ischaemia and reperfusion. In acute open-thorax experiments in anaesthetised pigs, pretreatment with low-dose carbon monoxide (5% increase in carboxyhaemoglobin) was conducted for 120 min before localised ischaemia (45 min) and reperfusion (60 min) was performed using a coronary snare. Metabolic and injury markers were collected by microdialysis sampling in the ventricular wall. Recovery of radio-marked calcium delivered locally by microperfusate was measured to assess carbon monoxide treatment effects during ischaemia/reperfusion on the intracellular calcium pool. Coronary occlusion and ischaemia/reperfusion were analysed for 16 animals (eight in each group). Changes in glucose, lactate and pyruvate from the ischaemic area were observed during ischaemia and reperfusion interventions, though there was no difference between carbon monoxide-treated and control groups during ischaemia or reperfusion. Similar results were observed for glycerol and microdialysate ⁴⁵Ca(2+) recovery. These findings show that a relatively low and clinically relevant dose of carbon monoxide did not seem to provide acute protection as indicated by metabolic, energy-related and injury markers in a porcine myocardial ischaemia/reperfusion experimental model. We conclude that protective effects of carbon monoxide related to ischaemia/reperfusion either require higher doses of carbon monoxide or occur later after reperfusion than the immediate time frame studied here. More study is needed to characterise the mechanism and time frame of carbon monoxide-related cytoprotection.
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Wang X, Wang Y, Lee SJ, Kim HP, Choi AM, Ryter SW. Carbon monoxide inhibits Fas activating antibody-induced apoptosis in endothelial cells. Med Gas Res 2011; 1:8. [PMID: 22146483 PMCID: PMC3231877 DOI: 10.1186/2045-9912-1-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2011] [Accepted: 05/18/2011] [Indexed: 12/18/2022] Open
Abstract
Background The extrinsic apoptotic pathway initiates when a death ligand, such as the Fas ligand, interacts with its cell surface receptor (ie., Fas/CD95), forming a death-inducing signaling complex (DISC). The Fas-dependent apoptotic pathway has been implicated in several models of lung or vascular injury. Carbon monoxide, an enzymatic product of heme oxygenase-1, exerts antiapoptotic effects at low concentration in vitro and in vivo. Methods Using mouse lung endothelial cells (MLEC), we examined the antiapoptotic potential of carbon monoxide against apoptosis induced by the Fas/CD95-activating antibody (Jo2). Carbon monoxide was applied to cell cultures in vitro. The expression and/or activation of apoptosis-related proteins and signaling intermediates were determined using Western Immunoblot and co-immunoprecipitation assays. Cell death was monitored by lactate dehydrogenase (LDH) release assays. Statistical significance was determined by student T-test and a value of P < 0.05 was considered significant. Results Treatment of MLEC with Fas-activating antibody (Jo2) induced cell death associated with the formation of the DISC, and activation of caspases (-8, -9, and -3), as well as the pro-apoptotic Bcl-2 family protein Bax. Exposure of MLEC to carbon monoxide inhibited Jo2-induced cell death, which correlated with the inhibition of DISC formation, cleavage of caspases-8, -9, and -3, and Bax activation. Carbon monoxide inhibited the phosphorylation of the Fas-associated death domain-containing protein, as well as its association with the DISC. Furthermore, carbon monoxide induced the expression of the antiapoptotic protein FLIP and increased its association with the DISC. CO-dependent cytoprotection against Fas mediated apoptosis in MLEC depended in part on activation of ERK1/2-dependent signaling. Conclusions Carbon monoxide has been proposed as a potential therapy for lung and other diseases based in part on its antiapoptotic effects in endothelial cells. In vitro, carbon monoxide may inhibit both Fas/caspase-8 and Bax-dependent apoptotic signaling pathways induced by Fas-activating antibody in endothelial cells. Strategies to block Fas-dependent apoptotic pathways may be useful in development of therapies for lung or vascular disorders.
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Affiliation(s)
- Xue Wang
- Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA.
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Camara AKS, Bienengraeber M, Stowe DF. Mitochondrial approaches to protect against cardiac ischemia and reperfusion injury. Front Physiol 2011; 2:13. [PMID: 21559063 PMCID: PMC3082167 DOI: 10.3389/fphys.2011.00013] [Citation(s) in RCA: 109] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2010] [Accepted: 03/24/2011] [Indexed: 12/18/2022] Open
Abstract
The mitochondrion is a vital component in cellular energy metabolism and intracellular signaling processes. Mitochondria are involved in a myriad of complex signaling cascades regulating cell death vs. survival. Importantly, mitochondrial dysfunction and the resulting oxidative and nitrosative stress are central in the pathogenesis of numerous human maladies including cardiovascular diseases, neurodegenerative diseases, diabetes, and retinal diseases, many of which are related. This review will examine the emerging understanding of the role of mitochondria in the etiology and progression of cardiovascular diseases and will explore potential therapeutic benefits of targeting the organelle in attenuating the disease process. Indeed, recent advances in mitochondrial biology have led to selective targeting of drugs designed to modulate or manipulate mitochondrial function, to the use of light therapy directed to the mitochondrial function, and to modification of the mitochondrial genome for potential therapeutic benefit. The approach to rationally treat mitochondrial dysfunction could lead to more effective interventions in cardiovascular diseases that to date have remained elusive. The central premise of this review is that if mitochondrial abnormalities contribute to the etiology of cardiovascular diseases (e.g., ischemic heart disease), alleviating the mitochondrial dysfunction will contribute to mitigating the severity or progression of the disease. To this end, this review will provide an overview of our current understanding of mitochondria function in cardiovascular diseases as well as the potential role for targeting mitochondria with potential drugs or other interventions that lead to protection against cell injury.
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Affiliation(s)
- Amadou K. S. Camara
- Department of Anesthesiology, Medical College of WisconsinMilwaukee, WI, USA
- Cardiovascular Research Center, Medical College of WisconsinMilwaukee, WI, USA
| | - Martin Bienengraeber
- Department of Anesthesiology, Medical College of WisconsinMilwaukee, WI, USA
- Department of Pharmacology and Toxicology, Medical College of WisconsinMilwaukee, WI, USA
| | - David F. Stowe
- Department of Anesthesiology, Medical College of WisconsinMilwaukee, WI, USA
- Cardiovascular Research Center, Medical College of WisconsinMilwaukee, WI, USA
- Department of Physiology, Medical College of WisconsinMilwaukee, WI, USA
- Research Service, Veterans Affairs Medical CenterMilwaukee, WI, USA
- Department of Biomedical Engineering, Marquette UniversityMilwaukee, WI, USA
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Goebel U, Siepe M, Schwer CI, Schibilsky D, Brehm K, Priebe HJ, Schlensak C, Loop T. Postconditioning of the Lungs with Inhaled Carbon Monoxide After Cardiopulmonary Bypass in Pigs. Anesth Analg 2011; 112:282-91. [DOI: 10.1213/ane.0b013e318203f591] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
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Abstract
Heme oxygenase-1 (HO-1) metabolizes heme to generate carbon monoxide (CO), biliverdin, and iron. Biliverdin is subsequently metabolized to bilirubin by biliverdin reductase. HO-1 has recently emerged as a promising therapeutic target in the treatment of vascular disease. Pharmacological induction or gene transfer of HO-1 ameliorates vascular dysfunction in animal models of atherosclerosis, post-angioplasty restenosis, vein graft stenosis, thrombosis, myocardial infarction, and hypertension, while inhibition of HO-1 activity or gene deletion exacerbates these disorders. The vasoprotection afforded by HO-1 is largely attributable to its end products: CO and the bile pigments, biliverdin and bilirubin. These end products exert potent anti-inflammatory, antioxidant, anti-apoptotic, and anti-thrombotic actions. In addition, CO and bile pigments act to preserve vascular homeostasis at sites of arterial injury by influencing the proliferation, migration, and adhesion of vascular smooth muscle cells, endothelial cells, endothelial progenitor cells, or leukocytes. Several strategies are currently being developed to target HO-1 in vascular disease. Pharmacological induction of HO-1 by heme derivatives, dietary antioxidants, or currently available drugs, is a promising near-term approach, while HO-1 gene delivery is a long-term therapeutic goal. Direct administration of CO via inhalation or through the use of CO-releasing molecules and/or CO-sensitizing agents provides an attractive alternative approach in targeting HO-1. Furthermore, delivery of bile pigments, either alone or in combination with CO, presents another avenue for protecting against vascular disease. Since HO-1 and its products are potentially toxic, a major challenge will be to devise clinically effective therapeutic modalities that target HO-1 without causing any adverse effects.
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Affiliation(s)
- William Durante
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri 65212, USA.
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Motterlini R, Otterbein LE. The therapeutic potential of carbon monoxide. Nat Rev Drug Discov 2010; 9:728-43. [PMID: 20811383 DOI: 10.1038/nrd3228] [Citation(s) in RCA: 1236] [Impact Index Per Article: 82.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Chen Q, Yin G, Stewart S, Hu Y, Lesnefsky EJ. Isolating the segment of the mitochondrial electron transport chain responsible for mitochondrial damage during cardiac ischemia. Biochem Biophys Res Commun 2010; 397:656-60. [PMID: 20529665 PMCID: PMC3045679 DOI: 10.1016/j.bbrc.2010.05.137] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2010] [Accepted: 05/27/2010] [Indexed: 02/07/2023]
Abstract
Ischemia damages the mitochondrial electron transport chain (ETC), mediated in part by damage generated by the mitochondria themselves. Mitochondrial damage resulting from ischemia, in turn, leads to cardiac injury during reperfusion. The goal of the present study was to localize the segment of the ETC that produces the ischemic mitochondrial damage. We tested if blockade of the proximal ETC at complex I differed from blockade distal in the chain at cytochrome oxidase. Isolated rabbit hearts were perfused for 15min followed by 30min stop-flow ischemia at 37 degrees C. Amobarbital (2.5mM) or azide (5mM) was used to block proximal (complex I) or distal (cytochrome oxidase) sites in the ETC. Time control hearts were buffer-perfused for 45min. Subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM) were isolated. Ischemia decreased cytochrome c content in SSM but not in IFM compared to time control. Blockade of electron transport at complex I preserved the cytochrome c content in SSM. In contrast, blockade of electron transport at cytochrome oxidase with azide did not retain cytochrome c in SSM during ischemia. Since blockade of electron transport at complex III also prevented cytochrome c loss during ischemia, the specific site that elicits mitochondrial damage during ischemia is likely located in the segment between complex III and cytochrome oxidase.
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Affiliation(s)
- Qun Chen
- Department of Medicine, Division of Cardiology, Case Western Reserve University, Cleveland, OH 44106
| | - Guotian Yin
- Department of Medicine, Division of Cardiology, Case Western Reserve University, Cleveland, OH 44106
| | - Sarah Stewart
- Department of Medicine, Division of Cardiology, Case Western Reserve University, Cleveland, OH 44106
| | - Ying Hu
- Department of Medicine, Division of Cardiology, Case Western Reserve University, Cleveland, OH 44106
| | - Edward J. Lesnefsky
- Department of Medicine, Division of Cardiology, Case Western Reserve University, Cleveland, OH 44106
- Medical Service, Louis Stokes Veterans Affairs Medical Center, Cleveland, OH 44106
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48
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Inhaled carbon monoxide prevents acute kidney injury in pigs after cardiopulmonary bypass by inducing a heat shock response. Anesth Analg 2010; 111:29-37. [PMID: 20519418 DOI: 10.1213/ane.0b013e3181e0cca4] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND Cardiopulmonary bypass (CPB) may be associated with acute kidney injury (AKI). Inhaled carbon monoxide (CO) is cyto- and organ-protective. We hypothesized that pretreatment with inhaled CO prevents CPB-associated AKI. METHODS Pigs (n = 38) were nonrandomly assigned to SHAM, standard CPB, pretreatment with inhaled CO (250 ppm, 1 hour) before SHAM or CPB, to pretreatment with quercetin (an inhibitor of the heat shock response), and to pretreatment with SnPPIX (an inhibitor of endogenously derived CO), before CO inhalation and CPB. The primary outcome variables were markers of AKI (urea, uric acid, creatinine, cystatin C, neutrophil gelatinase-associated lipocalin, interleukin-6, tumor necrosis factor-alpha), which were determined 120 minutes after CPB. Secondary outcome variables were heat shock protein (HSP)-70 and heme oxygenase-1 protein expressions as indicators of CO-mediated heat shock response. RESULTS Pretreatment with inhaled CO attenuated (all P < 0.001) CPB-associated, (1) increases in serum concentrations of cystatin C (64 +/- 14 vs 28 +/- 9 ng/mL), neutrophil gelatinase-associated lipocalin (391 +/- 65 vs 183 +/- 56 ng/mL), renal tumor necrosis factor-alpha (450 +/- 73 vs 179 +/- 110 pg/mL), and interleukin-6 (483 +/- 102 vs 125 +/- 67 pg/mL); (2) increase in renal caspase-3 activity (550 +/- 66 vs 259 +/- 52 relative fluorescent units); and (3) histological evidence of AKI. These effects were accompanied by activation of HSP-70 (196 +/- 64 vs 554 +/- 149 ng/mL, P < 0.001). Pretreatment with the heat shock response inhibitor quercetin counteracted the CO-associated biochemical and histological renoprotective effects (all P < 0.001), whereas the heme oxygenase inhibitor SnPPIX only partially counteracted the CO-associated renoprotection and the activation of the heat shock response. CONCLUSIONS CO treatment before CPB was associated with evidence of renoprotection, demonstrated by fewer histological injuries and decreased cystatin C concentrations. The findings that the antiinflammatory and antiapoptotic effects of CO were accompanied by activation of HSP-70, which in turn were reversed by quercetin, suggest that renoprotection by pretreatment with inhaled CO before CPB is mediated by activation of the renal heat shock response.
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Soni H, Patel P, Rath AC, Jain M, Mehta AA. Cardioprotective effect with carbon monoxide releasing molecule-2 (CORM-2) in isolated perfused rat heart: Role of coronary endothelium and underlying mechanism. Vascul Pharmacol 2010; 53:68-76. [PMID: 20399902 DOI: 10.1016/j.vph.2010.04.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2010] [Revised: 03/12/2010] [Accepted: 04/06/2010] [Indexed: 10/19/2022]
Abstract
Although the cardioprotective role of carbon monoxide (CO) has been studied against myocardial ischemia-reperfusion (I/R) injury, the role of coronary endothelium and underlying mechanism in carbon monoxide-induced cardioprotection is not well understood in isolated heart. The present study was designed to determine the role of coronary endothelium in CORM-2-mediated cardioprotection during I/R injury in isolated rat heart. Preconditioning with 30microM/l and 50microM/l of CORM-2 for 10min markedly reduced lactate dehydrogenase (LDH) and creatinin kinase (CK) levels in coronary effluent after global ischemia. There was also a significant improvement in coronary flow rate, heart rate, cardiodynamic parameters and marked attenuation in infarct size. However, protective effect was abolished when hearts were pretreated with 100microM CORM-2. We observed that pretreatment with L-NAME (100microM/l), a nitric oxide synthase (NOS) inhibitor did not affect protection by CORM-2 (50microM/l). On the other hand pretreatment with Triton X-100 (0.05% for 20s) to denude endothelium before CORM-2 treatment followed by I/R injury showed similar cardioprotection. Moreover, pretreatment with K(ATP) channel inhibitor, glibenclamide almost completely reversed the cardioprotective effect of CORM-2 in endothelium-denuded hearts. These results indicate that cardioprotection by CORM-2 is highly concentration-dependent, independent of coronary endothelium and cardioprotective effect might be attributed to the activation of K(ATP) channel present on vascular smooth muscle cell (VSMC).
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Affiliation(s)
- Hitesh Soni
- Zydus Research Centre (ZRC communication no. # 302), Sarkhej-Bavla N.H 8A Moraiya, Ahmedabad-382210, India
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