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Roslan A, Paulus K, Yang J, Matt L, Bischof H, Längst N, Schanz S, Luczak A, Cruz Santos M, Burgstaller S, Skrabak D, Bork NI, Malli R, Schmidtko A, Gawaz M, Nikolaev VO, Ruth P, Ehinger R, Lukowski R. Slack K+ channels confer protection against myocardial ischaemia/reperfusion injury. Cardiovasc Res 2025; 121:174-189. [PMID: 39102831 DOI: 10.1093/cvr/cvae155] [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: 11/03/2023] [Revised: 04/26/2024] [Accepted: 06/01/2024] [Indexed: 08/07/2024] Open
Abstract
AIMS Na+-activated Slack potassium (K+) channels are increasingly recognized as regulators of neuronal activity, yet little is known about their role in the cardiovascular system. Slack activity increases when intracellular Na+ concentration ([Na+]i) reaches pathophysiological levels. Elevated [Na+]i is a major determinant of the ischaemia and reperfusion (I/R)-induced myocardial injury; thus, we hypothesized that Slack plays a role under these conditions. METHODS AND RESULTS K+ currents in cardiomyocytes (CMs) obtained from wildtype but not from global Slack knockout mice were sensitive to electrical inactivation of voltage-sensitive Na+ channels. Live-cell imaging demonstrated that K+ fluxes across the sarcolemma rely on Slack, while the depolarized resting membrane potential in Slack-deficient CMs led to excessive cytosolic Ca2+ accumulation and finally to hypoxia/reoxygenation-induced cell death. Cardiac damage in an in vivo model of I/R was exacerbated in global and CM-specific conditional Slack mutants and largely insensitive to mechanical conditioning manoeuvres. Finally, the protection conferred by mitochondrial ATP-sensitive K+ (mitoKATP) channels required functional Slack in CMs. CONCLUSION Collectively, our study provides evidence for Slack's crucial involvement in the ion homeostasis of no or low O2-stressed CMs. Thereby, Slack activity opposes the I/R-induced fatal Ca2+-uptake to CMs supporting the cardioprotective signaling attributed to mitoKATP function.
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Affiliation(s)
- Anna Roslan
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, Auf der Morgenstelle 8, University of Tuebingen, 72076 Tuebingen, Germany
| | - Katharina Paulus
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, Auf der Morgenstelle 8, University of Tuebingen, 72076 Tuebingen, Germany
| | - Jiaqi Yang
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, Auf der Morgenstelle 8, University of Tuebingen, 72076 Tuebingen, Germany
| | - Lucas Matt
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, Auf der Morgenstelle 8, University of Tuebingen, 72076 Tuebingen, Germany
| | - Helmut Bischof
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, Auf der Morgenstelle 8, University of Tuebingen, 72076 Tuebingen, Germany
| | - Natalie Längst
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, Auf der Morgenstelle 8, University of Tuebingen, 72076 Tuebingen, Germany
| | - Sophia Schanz
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, Auf der Morgenstelle 8, University of Tuebingen, 72076 Tuebingen, Germany
| | - Annika Luczak
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, Auf der Morgenstelle 8, University of Tuebingen, 72076 Tuebingen, Germany
| | - Melanie Cruz Santos
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, Auf der Morgenstelle 8, University of Tuebingen, 72076 Tuebingen, Germany
| | - Sandra Burgstaller
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, Auf der Morgenstelle 8, University of Tuebingen, 72076 Tuebingen, Germany
| | - David Skrabak
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, Auf der Morgenstelle 8, University of Tuebingen, 72076 Tuebingen, Germany
| | - Nadja I Bork
- Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Roland Malli
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, and Center for Medical Research, CF Bioimaging, Medical University of Graz, Graz, Austria
| | - Achim Schmidtko
- Institute of Pharmacology and Clinical Pharmacy, Goethe-Universität Frankfurt a.M., Frankfurt a.M., Germany
| | - Meinrad Gawaz
- Department of Cardiology & Cardiovascular Diseases, University Hospital Tuebingen, Tuebingen, Germany
| | - Viacheslav O Nikolaev
- Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Peter Ruth
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, Auf der Morgenstelle 8, University of Tuebingen, 72076 Tuebingen, Germany
| | - Rebekka Ehinger
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, Auf der Morgenstelle 8, University of Tuebingen, 72076 Tuebingen, Germany
| | - Robert Lukowski
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, Auf der Morgenstelle 8, University of Tuebingen, 72076 Tuebingen, Germany
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Qu C, Tan X, Hu Q, Tang J, Wang Y, He C, He Z, Li B, Fu X, Du Q. A systematic review of astragaloside IV effects on animal models of diabetes mellitus and its complications. Heliyon 2024; 10:e26863. [PMID: 38439832 PMCID: PMC10909731 DOI: 10.1016/j.heliyon.2024.e26863] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 02/17/2024] [Accepted: 02/21/2024] [Indexed: 03/06/2024] Open
Abstract
Context Diabetes mellitus (DM) is one of the fastest-growing diseases worldwide; however, its pathogenesis remains unclear. Complications seriously affect the quality of life of patients in the later stages of diabetes, ultimately leading to suffering. Natural small molecules are an important source of antidiabetic agents. Objective Astragaloside IV (AS-IV) is an active ingredient of Astragalus mongholicus (Fisch.) Bunge. We reviewed the efficacy and mechanism of action of AS-IV in animal and cellular models of diabetes and the mechanism of action of AS-IV on diabetic complications in animal and cellular models. We also summarized the safety of AS-IV and provided ideas and rationales for its future clinical application. Methods Articles on the intervention in DM and its complications using AS-IV, such as those published in SCIENCE, PubMed, Springer, ACS, SCOPUS, and CNKI from the establishment of the database to February 2022, were reviewed. The following points were systematically summarized: dose/concentration, route of administration, potential mechanisms, and efficacy of AS-IV in animal models of DM and its complications. Results AS-IV has shown therapeutic effects in animal models of DM, such as alleviating gestational diabetes, delaying diabetic nephropathy, preventing myocardial cell apoptosis, and inhibiting vascular endothelial dysfunction; however, the potential effects of AS-IV on DM should be investigated. Conclusion AS-IV is a potential drug for the treatment of diabetes and its complications, including diabetic vascular disease, cardiomyopathy, retinopathy, peripheral neuropathy, and nephropathy. In addition, preclinical toxicity studies indicate that it appears to be safe, but the safe human dose limit is yet to be determined, and formal assessments of adverse drug reactions among humans need to be further investigated. However, additional formulations or structural modifications are required to improve the pharmacokinetic parameters and facilitate the clinical use of AS-IV.
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Affiliation(s)
- Caiyan Qu
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
- Nanjiang County Hospital of Chinese Medicine, Bazhong, 635600, China
| | - Xiyue Tan
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Qichao Hu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Jiao Tang
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Yangyang Wang
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Caiying He
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - ZiJia He
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Bin Li
- Department of Geriatrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Xiaoxu Fu
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Quanyu Du
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Chengdu, 610072, China
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3
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Yalaz C, Bridges E, Alham NK, Zois CE, Chen J, Bensaad K, Miar A, Pires E, Muschel RJ, McCullagh JSO, Harris AL. Cone photoreceptor phosphodiesterase PDE6H inhibition regulates cancer cell growth and metabolism, replicating the dark retina response. Cancer Metab 2024; 12:5. [PMID: 38350962 PMCID: PMC10863171 DOI: 10.1186/s40170-023-00326-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 11/24/2023] [Indexed: 02/15/2024] Open
Abstract
BACKGROUND PDE6H encodes PDE6γ', the inhibitory subunit of the cGMP-specific phosphodiesterase 6 in cone photoreceptors. Inhibition of PDE6, which has been widely studied for its role in light transduction, increases cGMP levels. The purpose of this study is to characterise the role of PDE6H in cancer cell growth. METHODS From an siRNA screen for 487 genes involved in metabolism, PDE6H was identified as a controller of cell cycle progression in HCT116 cells. Role of PDE6H in cancer cell growth and metabolism was studied through the effects of its depletion on levels of cell cycle controllers, mTOR effectors, metabolite levels, and metabolic energy assays. Effect of PDE6H deletion on tumour growth was also studied in a xenograft model. RESULTS PDE6H knockout resulted in an increase of intracellular cGMP levels, as well as changes to the levels of nucleotides and key energy metabolism intermediates. PDE6H knockdown induced G1 cell cycle arrest and cell death and reduced mTORC1 signalling in cancer cell lines. Both knockdown and knockout of PDE6H resulted in the suppression of mitochondrial function. HCT116 xenografts revealed that PDE6H deletion, as well as treatment with the PDE5/6 inhibitor sildenafil, slowed down tumour growth and improved survival, while sildenafil treatment did not have an additive effect on slowing the growth of PDE6γ'-deficient tumours. CONCLUSIONS Our results indicate that the changes in cGMP and purine pools, as well as mitochondrial function which is observed upon PDE6γ' depletion, are independent of the PKG pathway. We show that in HCT116, PDE6H deletion replicates many effects of the dark retina response and identify PDE6H as a new target in preventing cancer cell proliferation and tumour growth.
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Affiliation(s)
- Ceren Yalaz
- Molecular Oncology Laboratories, Department of Medical Oncology, John Radcliffe Hospital, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
| | - Esther Bridges
- Molecular Oncology Laboratories, Department of Medical Oncology, John Radcliffe Hospital, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK
| | - Nasullah K Alham
- Department of Engineering Science, Institute of Biomedical Engineering (IBME), University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK
| | - Christos E Zois
- Molecular Oncology Laboratories, Department of Medical Oncology, John Radcliffe Hospital, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK
| | - Jianzhou Chen
- Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK
| | - Karim Bensaad
- Molecular Oncology Laboratories, Department of Medical Oncology, John Radcliffe Hospital, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK
| | - Ana Miar
- Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK
| | - Elisabete Pires
- Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK
| | - Ruth J Muschel
- Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK
| | - James S O McCullagh
- Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK
| | - Adrian L Harris
- Molecular Oncology Laboratories, Department of Medical Oncology, John Radcliffe Hospital, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK
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Russo I, Barale C, Melchionda E, Penna C, Pagliaro P. Platelets and Cardioprotection: The Role of Nitric Oxide and Carbon Oxide. Int J Mol Sci 2023; 24:ijms24076107. [PMID: 37047079 PMCID: PMC10094148 DOI: 10.3390/ijms24076107] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 03/16/2023] [Accepted: 03/21/2023] [Indexed: 04/14/2023] Open
Abstract
Nitric oxide (NO) and carbon monoxide (CO) represent a pair of biologically active gases with an increasingly well-defined range of effects on circulating platelets. These gases interact with platelets and cells in the vessels and heart and exert fundamentally similar biological effects, albeit through different mechanisms and with some peculiarity. Within the cardiovascular system, for example, the gases are predominantly vasodilators and exert antiaggregatory effects, and are protective against damage in myocardial ischemia-reperfusion injury. Indeed, NO is an important vasodilator acting on vascular smooth muscle and is able to inhibit platelet activation. NO reacts with superoxide anion (O2(-•)) to form peroxynitrite (ONOO(-)), a nitrosating agent capable of inducing oxidative/nitrative signaling and stress both at cardiovascular, platelet, and plasma levels. CO reduces platelet reactivity, therefore it is an anticoagulant, but it also has some cardioprotective and procoagulant properties. This review article summarizes current knowledge on the platelets and roles of gas mediators (NO, and CO) in cardioprotection. In particular, we aim to examine the link and interactions between platelets, NO, and CO and cardioprotective pathways.
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Affiliation(s)
- Isabella Russo
- Department of Clinical and Biological Sciences of Turin University, Orbassano, I-10043 Turin, Italy
| | - Cristina Barale
- Department of Clinical and Biological Sciences of Turin University, Orbassano, I-10043 Turin, Italy
| | - Elena Melchionda
- Department of Clinical and Biological Sciences of Turin University, Orbassano, I-10043 Turin, Italy
| | - Claudia Penna
- Department of Clinical and Biological Sciences of Turin University, Orbassano, I-10043 Turin, Italy
| | - Pasquale Pagliaro
- Department of Clinical and Biological Sciences of Turin University, Orbassano, I-10043 Turin, Italy
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Pun-García A, Clemente-Moragón A, Villena-Gutierrez R, Gómez M, Sanz-Rosa D, Díaz-Guerra A, Prados B, Medina JP, Montó F, Ivorra MD, Márquez-López C, Cannavo A, Bernal JA, Koch WJ, Fuster V, de la Pompa JL, Oliver E, Ibanez B. Beta-3 adrenergic receptor overexpression reverses aortic stenosis-induced heart failure and restores balanced mitochondrial dynamics. Basic Res Cardiol 2022; 117:62. [PMID: 36445563 PMCID: PMC9708808 DOI: 10.1007/s00395-022-00966-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 10/31/2022] [Accepted: 10/31/2022] [Indexed: 11/30/2022]
Abstract
Aortic stenosis (AS) is associated with left ventricular (LV) hypertrophy and heart failure (HF). There is a lack of therapies able to prevent/revert AS-induced HF. Beta3 adrenergic receptor (β3AR) signaling is beneficial in several forms of HF. Here, we studied the potential beneficial effect of β3AR overexpression on AS-induced HF. Selective β3AR stimulation had a positive inotropic effect. Transgenic mice constitutively overexpressing human β3AR in the heart (c-hβ3tg) were protected from the development of HF in response to induced AS, and against cardiomyocyte mitochondrial dysfunction (fragmented mitochondria with remodeled cristae and metabolic reprogramming featuring altered substrate use). Similar beneficial effects were observed in wild-type mice inoculated with adeno-associated virus (AAV9) inducing cardiac-specific overexpression of human β3AR before AS induction. Moreover, AAV9-hβ3AR injection into wild-type mice at late disease stages, when cardiac hypertrophy and metabolic reprogramming are already advanced, reversed the HF phenotype and restored balanced mitochondrial dynamics, demonstrating the potential of gene-therapy-mediated β3AR overexpression in AS. Mice with cardiac specific ablation of Yme1l (cYKO), characterized by fragmented mitochondria, showed an increased mortality upon AS challenge. AAV9-hβ3AR injection in these mice before AS induction reverted the fragmented mitochondria phenotype and rescued them from death. In conclusion, our results step out that β3AR overexpression might have translational potential as a therapeutic strategy in AS-induced HF.
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Affiliation(s)
- Andrés Pun-García
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), IIS-Fundación Jiménez Díaz University Hospital, Melchor Fernandez Almagro, 3, 28029, Madrid, Spain
- CIBERCV, Madrid, Spain
| | - Agustín Clemente-Moragón
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), IIS-Fundación Jiménez Díaz University Hospital, Melchor Fernandez Almagro, 3, 28029, Madrid, Spain
- CIBERCV, Madrid, Spain
| | - Rocio Villena-Gutierrez
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), IIS-Fundación Jiménez Díaz University Hospital, Melchor Fernandez Almagro, 3, 28029, Madrid, Spain
| | - Monica Gómez
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), IIS-Fundación Jiménez Díaz University Hospital, Melchor Fernandez Almagro, 3, 28029, Madrid, Spain
| | - David Sanz-Rosa
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), IIS-Fundación Jiménez Díaz University Hospital, Melchor Fernandez Almagro, 3, 28029, Madrid, Spain
- CIBERCV, Madrid, Spain
- Universidad Europea de Madrid, Madrid, Spain
| | - Anabel Díaz-Guerra
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), IIS-Fundación Jiménez Díaz University Hospital, Melchor Fernandez Almagro, 3, 28029, Madrid, Spain
| | - Belén Prados
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), IIS-Fundación Jiménez Díaz University Hospital, Melchor Fernandez Almagro, 3, 28029, Madrid, Spain
- CIBERCV, Madrid, Spain
- Intercellular Signalling in Cardiovascular Development and Disease Laboratory, CNIC, Madrid, Spain
| | - Juan Pablo Medina
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), IIS-Fundación Jiménez Díaz University Hospital, Melchor Fernandez Almagro, 3, 28029, Madrid, Spain
- Cardiology Department, IIS-Fundación Jiménez Díaz University Hospital, Madrid, Spain
| | - Fermí Montó
- Departamento de Farmacología, Facultad de Farmacia, ERI BIOTECMED, Universitat de València, Burjassot, Spain
| | - Maria Dolores Ivorra
- Departamento de Farmacología, Facultad de Farmacia, ERI BIOTECMED, Universitat de València, Burjassot, Spain
| | - Cristina Márquez-López
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), IIS-Fundación Jiménez Díaz University Hospital, Melchor Fernandez Almagro, 3, 28029, Madrid, Spain
| | - Alessandro Cannavo
- Center for Translational Medicine and Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
- Department of Translational Medical Sciences, Federico II University of Naples, Naples, Italy
| | - Juan A Bernal
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), IIS-Fundación Jiménez Díaz University Hospital, Melchor Fernandez Almagro, 3, 28029, Madrid, Spain
- CIBERCV, Madrid, Spain
| | - Walter J Koch
- Center for Translational Medicine and Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Valentin Fuster
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), IIS-Fundación Jiménez Díaz University Hospital, Melchor Fernandez Almagro, 3, 28029, Madrid, Spain
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - José Luis de la Pompa
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), IIS-Fundación Jiménez Díaz University Hospital, Melchor Fernandez Almagro, 3, 28029, Madrid, Spain
- CIBERCV, Madrid, Spain
- Intercellular Signalling in Cardiovascular Development and Disease Laboratory, CNIC, Madrid, Spain
| | - Eduardo Oliver
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), IIS-Fundación Jiménez Díaz University Hospital, Melchor Fernandez Almagro, 3, 28029, Madrid, Spain
- CIBERCV, Madrid, Spain
- Centro de Investigaciones Biológicas Margarita Salas (CIB), CSIC, Madrid, Spain
| | - Borja Ibanez
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), IIS-Fundación Jiménez Díaz University Hospital, Melchor Fernandez Almagro, 3, 28029, Madrid, Spain.
- CIBERCV, Madrid, Spain.
- Cardiology Department, IIS-Fundación Jiménez Díaz University Hospital, Madrid, Spain.
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Maslov LN, Naryzhnaya NV, Sementsov AS, Derkachev IA, Gusakova SV, Sarybaev A. Role of Nitric Oxide Synthase in the Infarct-Limiting Effect of Normobaric Hypoxia. J EVOL BIOCHEM PHYS+ 2022. [DOI: 10.1134/s0022093022040202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Abramicheva PA, Plotnikov EY. Hormonal Regulation of Renal Fibrosis. Life (Basel) 2022; 12:737. [PMID: 35629404 PMCID: PMC9143586 DOI: 10.3390/life12050737] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/11/2022] [Accepted: 05/13/2022] [Indexed: 11/16/2022] Open
Abstract
Fibrosis is a severe complication of many acute and chronic kidney pathologies. According to current concepts, an imbalance in the synthesis and degradation of the extracellular matrix by fibroblasts is considered the key cause of the induction and progression of fibrosis. Nevertheless, inflammation associated with the damage of tissue cells is among the factors promoting this pathological process. Most of the mechanisms accompanying fibrosis development are controlled by various hormones, which makes humoral regulation an attractive target for therapeutic intervention. In this vein, it is particularly interesting that the kidney is the source of many hormones, while other hormones regulate renal functions. The normal kidney physiology and pathogenesis of many kidney diseases are sex-dependent and thus modulated by sex hormones. Therefore, when choosing therapy, it is necessary to focus on the sex-associated characteristics of kidney functioning. In this review, we considered renal fibrosis from the point of view of vasoactive and reproductive hormone imbalance. The hormonal therapy possibilities for the treatment or prevention of kidney fibrosis are also discussed.
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Affiliation(s)
- Polina A. Abramicheva
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia;
| | - Egor Y. Plotnikov
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia;
- Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia
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Boulghobra D, Dubois M, Alpha-Bazin B, Coste F, Olmos M, Gayrard S, Bornard I, Meyer G, Gaillard JC, Armengaud J, Reboul C. Increased protein S-nitrosylation in mitochondria: a key mechanism of exercise-induced cardioprotection. Basic Res Cardiol 2021; 116:66. [PMID: 34940922 DOI: 10.1007/s00395-021-00906-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 12/16/2021] [Accepted: 12/17/2021] [Indexed: 12/13/2022]
Abstract
Endothelial nitric oxide synthase (eNOS) activation in the heart plays a key role in exercise-induced cardioprotection during ischemia-reperfusion, but the underlying mechanisms remain unknown. We hypothesized that the cardioprotective effect of exercise training could be explained by the re-localization of eNOS-dependent nitric oxide (NO)/S-nitrosylation signaling to mitochondria. By comparing exercised (5 days/week for 5 weeks) and sedentary Wistar rats, we found that exercise training increased eNOS level and activation by phosphorylation (at serine 1177) in mitochondria, but not in the cytosolic subfraction of cardiomyocytes. Using confocal microscopy, we confirmed that NO production in mitochondria was increased in response to H2O2 exposure in cardiomyocytes from exercised but not sedentary rats. Moreover, by S-nitrosoproteomic analysis, we identified several key S-nitrosylated proteins involved in mitochondrial function and cardioprotection. In agreement, we also observed that the increase in Ca2+ retention capacity by mitochondria isolated from the heart of exercised rats was abolished by exposure to the NOS inhibitor L-NAME or to the reducing agent ascorbate, known to denitrosylate proteins. Pre-incubation with ascorbate or L-NAME also increased mitochondrial reactive oxygen species production in cardiomyocytes from exercised but not from sedentary animals. We confirmed these results using isolated hearts perfused with L-NAME before ischemia-reperfusion. Altogether, these results strongly support the hypothesis that exercise training increases eNOS/NO/S-nitrosylation signaling in mitochondria, which might represent a key mechanism of exercise-induced cardioprotection.
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Affiliation(s)
| | | | - Béatrice Alpha-Bazin
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), SPI, 30200, Bagnols-sur-Cèze, France
| | - Florence Coste
- LAPEC EA-4278, Avignon Université, 84000, Avignon, France
| | - Maxime Olmos
- LAPEC EA-4278, Avignon Université, 84000, Avignon, France
| | | | | | - Gregory Meyer
- LAPEC EA-4278, Avignon Université, 84000, Avignon, France
| | - Jean-Charles Gaillard
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), SPI, 30200, Bagnols-sur-Cèze, France
| | - Jean Armengaud
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), SPI, 30200, Bagnols-sur-Cèze, France
| | - Cyril Reboul
- LAPEC EA-4278, Avignon Université, 84000, Avignon, France. .,Cardiovascular Physiology Laboratory, UPR4278, UFR Sciences Technologies Santé, Centre INRAE-Site Agroparc, 228 route de l'Aérodrome, 84914, Avignon Cedex 9, France.
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Lukowski R, Cruz Santos M, Kuret A, Ruth P. cGMP and mitochondrial K + channels-Compartmentalized but closely connected in cardioprotection. Br J Pharmacol 2021; 179:2344-2360. [PMID: 33991427 DOI: 10.1111/bph.15536] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 05/05/2021] [Accepted: 05/07/2021] [Indexed: 01/01/2023] Open
Abstract
The 3',5'-cGMP pathway triggers cytoprotective responses and improves cardiomyocyte survival during myocardial ischaemia and reperfusion (I/R) injury. These beneficial effects were attributed to NO-sensitive GC induced cGMP production leading to activation of cGMP-dependent protein kinase I (cGKI). cGKI in turn phosphorylates many substrates, which eventually facilitate opening of mitochondrial ATP-sensitive potassium channels (mitoKATP ) and Ca2+ -activated potassium channels of the BK type (mitoBK). Accordingly, agents activating mitoKATP or mitoBK provide protection against I/R-induced damages. Here, we provide an up-to-date summary of the infarct-limiting actions exhibited by the GC/cGMP axis and discuss how mitoKATP and mitoBK, which are present at the inner mitochondrial membrane, confer mito- and cytoprotective effects on cardiomyocytes exposed to I/R injury. In view of this, we believe that the functional connection between the cGMP cascade and mitoK+ channels should be exploited further as adjunct to reperfusion therapy in myocardial infarction.
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Affiliation(s)
- Robert Lukowski
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, Tuebingen, Germany
| | - Melanie Cruz Santos
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, Tuebingen, Germany
| | - Anna Kuret
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, Tuebingen, Germany
| | - Peter Ruth
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, Tuebingen, Germany
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10
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Lee H, Jose PA. Coordinated Contribution of NADPH Oxidase- and Mitochondria-Derived Reactive Oxygen Species in Metabolic Syndrome and Its Implication in Renal Dysfunction. Front Pharmacol 2021; 12:670076. [PMID: 34017260 PMCID: PMC8129499 DOI: 10.3389/fphar.2021.670076] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 04/14/2021] [Indexed: 12/16/2022] Open
Abstract
Metabolic syndrome (MetS), a complex of interrelated risk factors for cardiovascular disease and diabetes, is comprised of central obesity (increased waist circumference), hyperglycemia, dyslipidemia (high triglyceride blood levels, low high-density lipoprotein blood levels), and increased blood pressure. Oxidative stress, caused by the imbalance between pro-oxidant and endogenous antioxidant systems, is the primary pathological basis of MetS. The major sources of reactive oxygen species (ROS) associated with MetS are nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases and mitochondria. In this review, we summarize the current knowledge regarding the generation of ROS from NADPH oxidases and mitochondria, discuss the NADPH oxidase- and mitochondria-derived ROS signaling and pathophysiological effects, and the interplay between these two major sources of ROS, which leads to chronic inflammation, adipocyte proliferation, insulin resistance, and other metabolic abnormalities. The mechanisms linking MetS and chronic kidney disease are not well known. The role of NADPH oxidases and mitochondria in renal injury in the setting of MetS, particularly the influence of the pyruvate dehydrogenase complex in oxidative stress, inflammation, and subsequent renal injury, is highlighted. Understanding the molecular mechanism(s) underlying MetS may lead to novel therapeutic approaches by targeting the pyruvate dehydrogenase complex in MetS and prevent its sequelae of chronic cardiovascular and renal diseases.
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Affiliation(s)
- Hewang Lee
- Department of Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States
| | - Pedro A Jose
- Department of Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States.,Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States
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11
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Liu J, Sun X, Jin H, Yan XL, Huang S, Guo ZN, Yang Y. Remote ischemic conditioning: A potential therapeutic strategy of type 2 diabetes. Med Hypotheses 2020; 146:110409. [PMID: 33277103 DOI: 10.1016/j.mehy.2020.110409] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 10/12/2020] [Accepted: 11/17/2020] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes (T2D) is one of the major public diseases which is characterized by peripheral insulin resistance (IR) and progressive pancreatic β-cell failure. While in the past few years, some new factors, such as inflammation, oxidative stress, immune responses and other potential pathways, have been identified to play critical roles in T2D, and thereby provide novel promising targets for the treatment of T2D. Remote ischemic conditioning (RIC) is a non-invasive and convenient operation performed by transient, repeated ischemia in distant place. Nowadays, RIC has been established as a potentially powerful therapeutic tool for many diseases, especially in I/R injuries. Through activating a series of neural, humoral and immune pathways, it can release multiple protective signals, which then regulating inflammation, oxidative stress, immune response and so on. Interestingly, several recent studies have discovered that the beneficial effects of RIC on I/R injuries might be abolished by T2D, wherein the higher basal levels of inflammation and oxidative stress, dysregulation of immune system and some potential pathways secondary to hyperglycemia may play critical roles. In contrast, a higher intensity of conditioning could restore the protective effects. Based on the overlapped mechanisms RIC and T2D performs, we provide a hypothesis that RIC may also play a protective role in T2D via targeting these signaling pathways.
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Affiliation(s)
- Jie Liu
- Stroke Center & Clinical Trial and Research Center for Stroke, Department of Neurology, the First Hospital of Jilin University, No. 1 Xinmin Street, Changchun 130021, China; China National Comprehensive Stroke Center, No. 1 Xinmin Street, Changchun 130021, China; Jilin Provincial Key Laboratory of Cerebrovascular Disease, No. 1 Xinmin Street, Changchun 130021, China
| | - Xin Sun
- Stroke Center & Clinical Trial and Research Center for Stroke, Department of Neurology, the First Hospital of Jilin University, No. 1 Xinmin Street, Changchun 130021, China; China National Comprehensive Stroke Center, No. 1 Xinmin Street, Changchun 130021, China
| | - Hang Jin
- Stroke Center & Clinical Trial and Research Center for Stroke, Department of Neurology, the First Hospital of Jilin University, No. 1 Xinmin Street, Changchun 130021, China; China National Comprehensive Stroke Center, No. 1 Xinmin Street, Changchun 130021, China
| | - Xiu-Li Yan
- Stroke Center & Clinical Trial and Research Center for Stroke, Department of Neurology, the First Hospital of Jilin University, No. 1 Xinmin Street, Changchun 130021, China
| | - Shuo Huang
- Stroke Center & Clinical Trial and Research Center for Stroke, Department of Neurology, the First Hospital of Jilin University, No. 1 Xinmin Street, Changchun 130021, China; China National Comprehensive Stroke Center, No. 1 Xinmin Street, Changchun 130021, China; Jilin Provincial Key Laboratory of Cerebrovascular Disease, No. 1 Xinmin Street, Changchun 130021, China
| | - Zhen-Ni Guo
- Stroke Center & Clinical Trial and Research Center for Stroke, Department of Neurology, the First Hospital of Jilin University, No. 1 Xinmin Street, Changchun 130021, China; China National Comprehensive Stroke Center, No. 1 Xinmin Street, Changchun 130021, China; Jilin Provincial Key Laboratory of Cerebrovascular Disease, No. 1 Xinmin Street, Changchun 130021, China.
| | - Yi Yang
- Stroke Center & Clinical Trial and Research Center for Stroke, Department of Neurology, the First Hospital of Jilin University, No. 1 Xinmin Street, Changchun 130021, China; China National Comprehensive Stroke Center, No. 1 Xinmin Street, Changchun 130021, China; Jilin Provincial Key Laboratory of Cerebrovascular Disease, No. 1 Xinmin Street, Changchun 130021, China.
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12
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Abstract
Heart failure (HF) is a common consequence of several cardiovascular diseases and is understood as a vicious cycle of cardiac and hemodynamic decline. The current inventory of treatments either alleviates the pathophysiological features (eg, cardiac dysfunction, neurohumoral activation, and ventricular remodeling) and/or targets any underlying pathologies (eg, hypertension and myocardial infarction). Yet, since these do not provide a cure, the morbidity and mortality associated with HF remains high. Therefore, the disease constitutes an unmet medical need, and novel therapies are desperately needed. Cyclic guanosine-3',5'-monophosphate (cGMP), synthesized by nitric oxide (NO)- and natriuretic peptide (NP)-responsive guanylyl cyclase (GC) enzymes, exerts numerous protective effects on cardiac contractility, hypertrophy, fibrosis, and apoptosis. Impaired cGMP signaling, which can occur after GC deactivation and the upregulation of cyclic nucleotide-hydrolyzing phosphodiesterases (PDEs), promotes cardiac dysfunction. In this study, we review the role that NO/cGMP and NP/cGMP signaling plays in HF. After considering disease etiology, the physiological effects of cGMP in the heart are discussed. We then assess the evidence from preclinical models and patients that compromised cGMP signaling contributes to the HF phenotype. Finally, the potential of pharmacologically harnessing cardioprotective cGMP to rectify the present paucity of effective HF treatments is examined.
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13
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Sadek MS, Cachorro E, El-Armouche A, Kämmerer S. Therapeutic Implications for PDE2 and cGMP/cAMP Mediated Crosstalk in Cardiovascular Diseases. Int J Mol Sci 2020; 21:E7462. [PMID: 33050419 PMCID: PMC7590001 DOI: 10.3390/ijms21207462] [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: 09/02/2020] [Revised: 10/07/2020] [Accepted: 10/08/2020] [Indexed: 12/11/2022] Open
Abstract
Phosphodiesterases (PDEs) are the principal superfamily of enzymes responsible for degrading the secondary messengers 3',5'-cyclic nucleotides cAMP and cGMP. Their refined subcellular localization and substrate specificity contribute to finely regulate cAMP/cGMP gradients in various cellular microdomains. Redistribution of multiple signal compartmentalization components is often perceived under pathological conditions. Thereby PDEs have long been pursued as therapeutic targets in diverse disease conditions including neurological, metabolic, cancer and autoimmune disorders in addition to numerous cardiovascular diseases (CVDs). PDE2 is a unique member of the broad family of PDEs. In addition to its capability to hydrolyze both cAMP and cGMP, PDE2 is the sole isoform that may be allosterically activated by cGMP increasing its cAMP hydrolyzing activity. Within the cardiovascular system, PDE2 serves as an integral regulator for the crosstalk between cAMP/cGMP pathways and thereby may couple chronically adverse augmented cAMP signaling with cardioprotective cGMP signaling. This review provides a comprehensive overview of PDE2 regulatory functions in multiple cellular components within the cardiovascular system and also within various subcellular microdomains. Implications for PDE2- mediated crosstalk mechanisms in diverse cardiovascular pathologies are discussed highlighting the prospective use of PDE2 as a potential therapeutic target in cardiovascular disorders.
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Affiliation(s)
| | | | - Ali El-Armouche
- Department of Pharmacology and Toxicology, Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany; (M.S.S.); (E.C.)
| | - Susanne Kämmerer
- Department of Pharmacology and Toxicology, Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany; (M.S.S.); (E.C.)
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14
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Wang M, Scott SR, Koniaris LG, Zimmers TA. Pathological Responses of Cardiac Mitochondria to Burn Trauma. Int J Mol Sci 2020; 21:ijms21186655. [PMID: 32932869 PMCID: PMC7554938 DOI: 10.3390/ijms21186655] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 09/04/2020] [Accepted: 09/08/2020] [Indexed: 12/18/2022] Open
Abstract
Despite advances in treatment and care, burn trauma remains the fourth most common type of traumatic injury. Burn-induced cardiac failure is a key factor for patient mortality, especially during the initial post-burn period (the first 24 to 48 h). Mitochondria, among the most important subcellular organelles in cardiomyocytes, are a central player in determining the severity of myocardial damage. Defects in mitochondrial function and structure are involved in pathogenesis of numerous myocardial injuries and cardiovascular diseases. In this article, we comprehensively review the current findings on cardiac mitochondrial pathological changes and summarize burn-impaired mitochondrial respiration capacity and energy supply, induced mitochondrial oxidative stress, and increased cell death. The molecular mechanisms underlying these alterations are discussed, along with the possible influence of other biological variables. We hope this review will provide useful information to explore potential therapeutic approaches that target mitochondria for cardiac protection following burn injury.
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Affiliation(s)
- Meijing Wang
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (S.R.S.); (L.G.K.); (T.A.Z.)
- Correspondence:
| | - Susan R. Scott
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (S.R.S.); (L.G.K.); (T.A.Z.)
| | - Leonidas G. Koniaris
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (S.R.S.); (L.G.K.); (T.A.Z.)
- Simon Cancer Center, Indiana University, Indianapolis, IN 46202, USA
- Indiana Center for Musculoskeletal Health, Indianopolis, IN 46202, USA
- Center for Cachexia Research Innovation and Therapy, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA
| | - Teresa A. Zimmers
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (S.R.S.); (L.G.K.); (T.A.Z.)
- Simon Cancer Center, Indiana University, Indianapolis, IN 46202, USA
- Indiana Center for Musculoskeletal Health, Indianopolis, IN 46202, USA
- Center for Cachexia Research Innovation and Therapy, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA
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15
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Klimova N, Fearnow A, Kristian T. Role of NAD +-Modulated Mitochondrial Free Radical Generation in Mechanisms of Acute Brain Injury. Brain Sci 2020; 10:brainsci10070449. [PMID: 32674501 PMCID: PMC7408119 DOI: 10.3390/brainsci10070449] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 06/30/2020] [Accepted: 07/09/2020] [Indexed: 12/15/2022] Open
Abstract
It is commonly accepted that mitochondria represent a major source of free radicals following acute brain injury or during the progression of neurodegenerative diseases. The levels of reactive oxygen species (ROS) in cells are determined by two opposing mechanisms—the one that produces free radicals and the cellular antioxidant system that eliminates ROS. Thus, the balance between the rate of ROS production and the efficiency of the cellular detoxification process determines the levels of harmful reactive oxygen species. Consequently, increase in free radical levels can be a result of higher rates of ROS production or due to the inhibition of the enzymes that participate in the antioxidant mechanisms. The enzymes’ activity can be modulated by post-translational modifications that are commonly altered under pathologic conditions. In this review we will discuss the mechanisms of mitochondrial free radical production following ischemic insult, mechanisms that protect mitochondria against free radical damage, and the impact of post-ischemic nicotinamide adenine mononucleotide (NAD+) catabolism on mitochondrial protein acetylation that affects ROS generation and mitochondrial dynamics. We propose a mechanism of mitochondrial free radical generation due to a compromised mitochondrial antioxidant system caused by intra-mitochondrial NAD+ depletion. Finally, the interplay between different mechanisms of mitochondrial ROS generation and potential therapeutic approaches are reviewed.
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Affiliation(s)
- Nina Klimova
- Veterans Affairs Maryland Health Center System, 10 North Greene Street, Baltimore, MD 21201, USA; (N.K.); (A.F.)
- Department of Anesthesiology and the Center for Shock, Trauma, and Anesthesiology Research (S.T.A.R.), University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Adam Fearnow
- Veterans Affairs Maryland Health Center System, 10 North Greene Street, Baltimore, MD 21201, USA; (N.K.); (A.F.)
| | - Tibor Kristian
- Veterans Affairs Maryland Health Center System, 10 North Greene Street, Baltimore, MD 21201, USA; (N.K.); (A.F.)
- Department of Anesthesiology and the Center for Shock, Trauma, and Anesthesiology Research (S.T.A.R.), University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Correspondence:
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16
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Andreadou I, Schulz R, Papapetropoulos A, Turan B, Ytrehus K, Ferdinandy P, Daiber A, Di Lisa F. The role of mitochondrial reactive oxygen species, NO and H 2 S in ischaemia/reperfusion injury and cardioprotection. J Cell Mol Med 2020; 24:6510-6522. [PMID: 32383522 PMCID: PMC7299678 DOI: 10.1111/jcmm.15279] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 03/04/2020] [Accepted: 03/08/2020] [Indexed: 12/12/2022] Open
Abstract
Redox signalling in mitochondria plays an important role in myocardial ischaemia/reperfusion (I/R) injury and in cardioprotection. Reactive oxygen and nitrogen species (ROS/RNS) modify cellular structures and functions by means of covalent changes in proteins including among others S‐nitros(yl)ation by nitric oxide (NO) and its derivatives, and S‐sulphydration by hydrogen sulphide (H2S). Many enzymes are involved in the mitochondrial formation and handling of ROS, NO and H2S under physiological and pathological conditions. In particular, the balance between formation and removal of reactive species is impaired during I/R favouring their accumulation. Therefore, various interventions aimed at decreasing mitochondrial ROS accumulation have been developed and have shown cardioprotective effects in experimental settings. However, ROS, NO and H2S play also a role in endogenous cardioprotection, as in the case of ischaemic pre‐conditioning, so that preventing their increase might hamper self‐defence mechanisms. The aim of the present review was to provide a critical analysis of formation and role of reactive species, NO and H2S in mitochondria, with a special emphasis on mechanisms of injury and protection that determine the fate of hearts subjected to I/R. The elucidation of the signalling pathways of ROS, NO and H2S is likely to reveal novel molecular targets for cardioprotection that could be modulated by pharmacological agents to prevent I/R injury.
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Affiliation(s)
- Ioanna Andreadou
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
| | - Rainer Schulz
- Institute for Physiology, Justus-Liebig University Giessen, Giessen, Germany
| | - Andreas Papapetropoulos
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
| | - Belma Turan
- Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Kirsti Ytrehus
- Department of Medical Biology, UiT The Arctic University of Norway, Tromso, Norway
| | - Peter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.,Pharmahungary Group, Szeged, Hungary
| | - Andreas Daiber
- Molecular Cardiology, Center for Cardiology 1, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Fabio Di Lisa
- Department of Biomedical Sciences, Università degli Studi di Padova, Padova, Italy
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17
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Severino P, D’Amato A, Pucci M, Infusino F, Birtolo LI, Mariani MV, Lavalle C, Maestrini V, Mancone M, Fedele F. Ischemic Heart Disease and Heart Failure: Role of Coronary Ion Channels. Int J Mol Sci 2020; 21:E3167. [PMID: 32365863 PMCID: PMC7246492 DOI: 10.3390/ijms21093167] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 04/28/2020] [Accepted: 04/28/2020] [Indexed: 01/09/2023] Open
Abstract
Heart failure is a complex syndrome responsible for high rates of death and hospitalization. Ischemic heart disease is one of the most frequent causes of heart failure and it is normally attributed to coronary artery disease, defined by the presence of one or more obstructive plaques, which determine a reduced coronary blood flow, causing myocardial ischemia and consequent heart failure. However, coronary obstruction is only an element of a complex pathophysiological process that leads to myocardial ischemia. In the literature, attention paid to the role of microcirculation, in the pathophysiology of ischemic heart disease and heart failure, is growing. Coronary microvascular dysfunction determines an inability of coronary circulation to satisfy myocardial metabolic demands, due to the imbalance of coronary blood flow regulatory mechanisms, including ion channels, leading to the development of hypoxia, fibrosis and tissue death, which may determine a loss of myocardial function, even beyond the presence of atherosclerotic epicardial plaques. For this reason, ion channels may represent the link among coronary microvascular dysfunction, ischemic heart disease and consequent heart failure.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Francesco Fedele
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155-00161 Rome, Italy; (P.S.); (A.D.); (M.P.); (F.I.); (L.I.B.); (M.V.M.); (C.L.); (V.M.); (M.M.)
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18
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Domondon M, Nikiforova AB, DeLeon-Pennell KY, Ilatovskaya DV. Regulation of mitochondria function by natriuretic peptides. Am J Physiol Renal Physiol 2019; 317:F1164-F1168. [PMID: 31509010 PMCID: PMC6879937 DOI: 10.1152/ajprenal.00384.2019] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 09/02/2019] [Accepted: 09/04/2019] [Indexed: 02/08/2023] Open
Abstract
Natriuretic peptides (NPs) are well known to promote renal Na+ excretion, counteracting the effects of the renin-angiotensin-aldosterone system. Thus, NPs serve as a key component in the maintenance of blood pressure, influencing fluid retention capabilities via osmoregulation. Recently, NPs have been shown to affect lipolysis and enhance lipid oxidation and mitochondrial respiration. Here, we provide an overview of current knowledge about the relationship between NPs and mitochondria-mediated processes such as reactive oxygen species production, Ca2+ signaling, and apoptosis. Establishing a clear physiological and mechanistic connection between NPs and mitochondria in the cardiovascular system will open new avenues of research aimed at understanding and potentially using it as a therapeutic target from a completely new angle.
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Affiliation(s)
- Mark Domondon
- Division of Nephrology, Medical University of South Carolina, Charleston, South Carolina
| | - Anna B Nikiforova
- Division of Nephrology, Medical University of South Carolina, Charleston, South Carolina
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, Russia
| | - Kristine Y DeLeon-Pennell
- Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
- Research Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina
| | - Daria V Ilatovskaya
- Division of Nephrology, Medical University of South Carolina, Charleston, South Carolina
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina
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19
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Nakamura T, Zhu G, Ranek MJ, Kokkonen-Simon K, Zhang M, Kim GE, Tsujita K, Kass DA. Prevention of PKG-1α Oxidation Suppresses Antihypertrophic/Antifibrotic Effects From PDE5 Inhibition but not sGC Stimulation. Circ Heart Fail 2019; 11:e004740. [PMID: 29545395 DOI: 10.1161/circheartfailure.117.004740] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Accepted: 01/17/2018] [Indexed: 12/21/2022]
Abstract
BACKGROUND Stimulation of sGC (soluble guanylate cyclase) or inhibition of PDE5 (phosphodiesterase type 5) activates PKG (protein kinase G)-1α to counteract cardiac hypertrophy and failure. PKG1α acts within localized intracellular domains; however, its oxidation at cysteine 42, linking homomonomers, alters this localization, impairing suppression of pathological cardiac stress. Because PDE5 and sGC reside in separate microdomains, we speculated that PKG1α oxidation might also differentially influence the effects from their pharmacological modulation. METHODS AND RESULTS Knock-in mice expressing a redox-dead PKG1α (PKG1αC42S) or littermate controls (PKG1αWT) were subjected to transaortic constriction to induce pressure overload and treated with a PDE5 inhibitor (sildenafil), sGC activator (BAY602770 [BAY]), or vehicle. In PKG1αWT controls, sildenafil and BAY similarly enhanced PKG activity and reduced pathological hypertrophy/fibrosis and cardiac dysfunction after transaortic constriction. However, sildenafil failed to protect the heart in PKG1αC42S, unlike BAY, which activated PKG and thereby facilitated protective effects. This corresponded with minimal PDE5 activation in PKG1αC42S exposed to transaortic constriction versus higher activity in controls and little colocalization of PDE5 with PKG1αC42S (versus colocalization with PKG1αWT) in stressed myocytes. CONCLUSIONS In the stressed heart and myocytes, PKG1α C42-disulfide formation contributes to PDE5 activation. This augments the pathological role of PDE5 and so in turn enhances the therapeutic impact from its inhibition. PKG1α oxidation does not change the benefits from sGC activation. This finding favors the use of sGC activators regardless of PKG1α oxidation and may help guide precision therapy leveraging the cyclic GMP/PKG pathway to treat heart disease.
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Affiliation(s)
- Taishi Nakamura
- From the Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (T.N., G.Z., M.J.R., K.K.-S., M.Z., G.E.K., D.A.K.); and Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan (T.N., K.T.)
| | - Guangshuo Zhu
- From the Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (T.N., G.Z., M.J.R., K.K.-S., M.Z., G.E.K., D.A.K.); and Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan (T.N., K.T.)
| | - Mark J Ranek
- From the Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (T.N., G.Z., M.J.R., K.K.-S., M.Z., G.E.K., D.A.K.); and Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan (T.N., K.T.)
| | - Kristen Kokkonen-Simon
- From the Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (T.N., G.Z., M.J.R., K.K.-S., M.Z., G.E.K., D.A.K.); and Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan (T.N., K.T.)
| | - Manling Zhang
- From the Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (T.N., G.Z., M.J.R., K.K.-S., M.Z., G.E.K., D.A.K.); and Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan (T.N., K.T.)
| | - Grace E Kim
- From the Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (T.N., G.Z., M.J.R., K.K.-S., M.Z., G.E.K., D.A.K.); and Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan (T.N., K.T.)
| | - Kenichi Tsujita
- From the Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (T.N., G.Z., M.J.R., K.K.-S., M.Z., G.E.K., D.A.K.); and Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan (T.N., K.T.)
| | - David A Kass
- From the Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (T.N., G.Z., M.J.R., K.K.-S., M.Z., G.E.K., D.A.K.); and Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan (T.N., K.T.).
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20
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Poderoso JJ, Helfenberger K, Poderoso C. The effect of nitric oxide on mitochondrial respiration. Nitric Oxide 2019; 88:61-72. [PMID: 30999001 DOI: 10.1016/j.niox.2019.04.005] [Citation(s) in RCA: 114] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 04/04/2019] [Accepted: 04/11/2019] [Indexed: 01/04/2023]
Abstract
This article reviews the interactions between nitric oxide (NO) and mitochondrial respiration. Mitochondrial ATP synthesis is responsible for virtually all energy production in mammals, and every other process in living organisms ultimately depends on that energy production. Furthermore, both necrosis and apoptosis, that summarize the main forms of cell death, are intimately linked to mitochondrial integrity. Endogenous and exogenous •NO inhibits mitochondrial respiration by different well-studied mechanisms and several nitrogen derivatives. Instantaneously, low concentrations of •NO, specifically and reversibly inhibit cytochrome c oxidase in competition with oxygen, in several tissues and cells in culture. Higher concentrations of •NO and its derivatives (peroxynitrite, nitrogen dioxide or nitrosothiols) can cause irreversible inhibition of the respiratory chain, uncoupling, permeability transition, and/or cell death. Peroxynitrite can cause opening of the permeability transition pore and opening of this pore causes loss of cytochrome c, which in turn might contribute to peroxynitrite-induced inhibition of respiration. Therefore, the inhibition of cytochrome c oxidase by •NO may be involved in the physiological and/or pathological regulation of respiration rate, and its affinity for oxygen, which depend on reactive nitrogen species formation, pH, proton motriz force and oxygen supply to tissues.
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Affiliation(s)
- Juan José Poderoso
- Universidad de Buenos Aires, Facultad de Medicina, Hospital de Clínicas "José de San Martín", Laboratorio Del Metabolismo Del Oxígeno, Buenos Aires, Argentina; CONICET-Universidad de Buenos Aires. Instituto de Inmunología, Genética y Metabolismo (INIGEM), Buenos Aires, Argentina
| | - Katia Helfenberger
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Bioquímica Humana, Paraguay 2155 5th Floor, Buenos Aires, Argentina; CONICET-Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
| | - Cecilia Poderoso
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Bioquímica Humana, Paraguay 2155 5th Floor, Buenos Aires, Argentina; CONICET-Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina.
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21
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Marck PV, Pierre SV. Na/K-ATPase Signaling and Cardiac Pre/Postconditioning with Cardiotonic Steroids. Int J Mol Sci 2018; 19:ijms19082336. [PMID: 30096873 PMCID: PMC6121447 DOI: 10.3390/ijms19082336] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 08/05/2018] [Accepted: 08/06/2018] [Indexed: 12/13/2022] Open
Abstract
The first reports of cardiac Na/K-ATPase signaling, published 20 years ago, have opened several major fields of investigations into the cardioprotective action of low/subinotropic concentrations of cardiotonic steroids (CTS). This review focuses on the protective cardiac Na/K-ATPase-mediated signaling triggered by low concentrations of ouabain and other CTS, in the context of the enduring debate over the use of CTS in the ischemic heart. Indeed, as basic and clinical research continues to support effectiveness and feasibility of conditioning interventions against ischemia/reperfusion injury in acute myocardial infarction (AMI), the mechanistic information available to date suggests that unique features of CTS-based conditioning could be highly suitable, alone /or as a combinatory approach.
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Affiliation(s)
- Pauline V Marck
- Marshall Institute for Interdisciplinary Research, Marshall University, Huntington, West Virginia, WV 25701, USA.
| | - Sandrine V Pierre
- Marshall Institute for Interdisciplinary Research, Marshall University, Huntington, West Virginia, WV 25701, USA.
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22
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cGMP at the centre of attention: emerging strategies for activating the cardioprotective PKG pathway. Basic Res Cardiol 2018; 113:24. [PMID: 29766323 PMCID: PMC5954070 DOI: 10.1007/s00395-018-0679-9] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Accepted: 04/04/2018] [Indexed: 12/22/2022]
Abstract
The nitric oxide (NO)-protein kinase G (PKG) pathway has been known for some time to be an important target for cardioprotection against ischaemia/reperfusion injury and heart failure. While many approaches for reducing infarct size in patients have failed in the past, the advent of novel drugs that modulate cGMP and its downstream targets shows very promising results in recent preclinical and clinical studies. Here, we review main aspects of the NO-PKG pathway in light of recent drug development and summarise potential cardioprotective strategies in which cGMP is the main player.
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23
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Hauerslev M, Mørk SR, Pryds K, Contractor H, Hansen J, Jespersen NR, Johnsen J, Heusch G, Kleinbongard P, Kharbanda R, Bøtker HE, Schmidt MR. Influence of long-term treatment with glyceryl trinitrate on remote ischemic conditioning. Am J Physiol Heart Circ Physiol 2018; 315:H150-H158. [PMID: 29569958 DOI: 10.1152/ajpheart.00114.2018] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Remote ischemic conditioning (RIC) protects against sustained myocardial ischemia. Because of overlapping mechanisms, this protection may be altered by glyceryl trinitrate (GTN), which is commonly used in the treatment of patients with chronic ischemic heart disease. We investigated whether long-term GTN treatment modifies the protection by RIC in the rat myocardium and human endothelium. We studied infarct size (IS) in rat hearts subjected to global ischemia-reperfusion (I/R) in vitro and endothelial function in healthy volunteers subjected to I/R of the upper arm. In addition to allocated treatment, rats were coadministered with reactive oxygen species (ROS) or nitric oxide (NO) scavengers. Rats and humans were randomized to 1) control, 2) RIC, 3) GTN, and 4) GTN + RIC. In protocols 3 and 4, rats and humans underwent long-term GTN treatment for 7 consecutive days, applied subcutaneously or 2 h daily transdermally. In rats, RIC and long-term GTN treatment reduced mean IS (18 ± 12%, P = 0.007 and 15 ± 5%, P = 0.002) compared with control (35 ± 13%). RIC and long-term GTN treatment in combination did not reduce IS (29 ± 12%, P = 0.55 vs. control). ROS and NO scavengers both attenuated IS reduction by RIC and long-term GTN treatment. In humans, I/R reduced endothelial function ( P = 0.01 vs. baseline). Separately, RIC and long-term GTN prevented the reduction in endothelial function caused by I/R; given in combination, prevention was lost. RIC and long-term GTN treatment both protect against rat myocardial and human endothelial I/R injury through ROS and NO-dependent mechanisms. However, when given in combination, RIC and long-term GTN treatment fail to confer protection. NEW & NOTEWORTHY Remote ischemic conditioning (RIC) and long-term glyceryl trinitrate (GTN) treatment protect against ischemia-reperfusion injury in both human endothelium and rat myocardium. However, combined application of RIC and long-term GTN treatment abolishes the individual protective effects of RIC and GTN treatment on ischemia-reperfusion injury, suggesting an interaction of clinical importance.
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Affiliation(s)
- Marie Hauerslev
- Department of Cardiology, Aarhus University Hospital , Aarhus , Denmark
| | - Sivagowry Rasalingam Mørk
- Department of Cardiology, Aarhus University Hospital , Aarhus , Denmark.,Department of Cardiovascular Medicine, University of Oxford , Oxford , United Kingdom
| | - Kasper Pryds
- Department of Cardiology, Aarhus University Hospital , Aarhus , Denmark.,Department of Cardiovascular Medicine, University of Oxford , Oxford , United Kingdom
| | - Hussain Contractor
- Department of Cardiovascular Medicine, University of Oxford , Oxford , United Kingdom
| | - Jan Hansen
- Department of Cardiology, Aarhus University Hospital , Aarhus , Denmark
| | | | - Jacob Johnsen
- Department of Cardiology, Aarhus University Hospital , Aarhus , Denmark
| | - Gerd Heusch
- Institute for Pathophysiology, West German Heart and Vascular Center, University School of Medicine Essen , Essen , Germany
| | - Petra Kleinbongard
- Institute for Pathophysiology, West German Heart and Vascular Center, University School of Medicine Essen , Essen , Germany
| | - Rajesh Kharbanda
- Department of Cardiovascular Medicine, University of Oxford , Oxford , United Kingdom
| | - Hans Erik Bøtker
- Department of Cardiology, Aarhus University Hospital , Aarhus , Denmark
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24
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Frankenreiter S, Bednarczyk P, Kniess A, Bork NI, Straubinger J, Koprowski P, Wrzosek A, Mohr E, Logan A, Murphy MP, Gawaz M, Krieg T, Szewczyk A, Nikolaev VO, Ruth P, Lukowski R. cGMP-Elevating Compounds and Ischemic Conditioning Provide Cardioprotection Against Ischemia and Reperfusion Injury via Cardiomyocyte-Specific BK Channels. Circulation 2017; 136:2337-2355. [PMID: 29051185 DOI: 10.1161/circulationaha.117.028723] [Citation(s) in RCA: 120] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 10/02/2017] [Indexed: 11/16/2022]
Abstract
BACKGROUND The nitric oxide-sensitive guanylyl cyclase/cGMP-dependent protein kinase type I signaling pathway can afford protection against the ischemia/reperfusion injury that occurs during myocardial infarction. Reportedly, voltage and Ca2+-activated K+ channels of the BK type are stimulated by cGMP/cGMP-dependent protein kinase type I, and recent ex vivo studies implicated that increased BK activity favors the survival of the myocardium at ischemia/reperfusion. It remains unclear, however, whether the molecular events downstream of cGMP involve BK channels present in cardiomyocytes or in other cardiac cell types. METHODS Gene-targeted mice with a cardiomyocyte- or smooth muscle cell-specific deletion of the BK (CMBK or SMBK knockouts) were subjected to the open-chest model of myocardial infarction. Infarct sizes of the conditional mutants were compared with litter-matched controls, global BK knockout, and wild-type mice. Cardiac damage was assessed after mechanical conditioning or pharmacological stimulation of the cGMP pathway and by using direct modulators of BK. Long-term outcome was studied with respect to heart functions and cardiac fibrosis in a chronic myocardial infarction model. RESULTS Global BK knockouts and CMBK knockouts, in contrast with SMBK knockouts, exhibited significantly larger infarct sizes compared with their respective controls. Ablation of CMBK resulted in higher serum levels of cardiac troponin I and elevated amounts of reactive oxygen species, lower phosphorylated extracellular receptor kinase and phosphorylated AKT levels and an increase in myocardial apoptosis. Moreover, CMBK was required to allow beneficial effects of both nitric oxide-sensitive guanylyl cyclase activation and inhibition of the cGMP-degrading phosphodiesterase-5, ischemic preconditioning, and postconditioning regimens. To this end, after 4 weeks of reperfusion, fibrotic tissue increased and myocardial strain echocardiography was significantly compromised in CMBK-deficient mice. CONCLUSIONS Lack of CMBK channels renders the heart more susceptible to ischemia/reperfusion injury, whereas the pathological events elicited by ischemia/reperfusion do not involve BK in vascular smooth muscle cells. BK seems to permit the protective effects triggered by cinaciguat, riociguat, and different phosphodiesterase-5 inhibitors and beneficial actions of ischemic preconditioning and ischemic postconditioning by a mechanism stemming primarily from cardiomyocytes. This study establishes mitochondrial CMBK channels as a promising target for limiting acute cardiac damage and adverse long-term events that occur after myocardial infarction.
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Affiliation(s)
- Sandra Frankenreiter
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, Germany (S.F., A.K., J.S., E.M., P.R., R.L.)
| | - Piotr Bednarczyk
- Department of Biophysics, Warsaw University of Life Sciences, Poland (P.B.)
| | - Angelina Kniess
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, Germany (S.F., A.K., J.S., E.M., P.R., R.L.)
| | - Nadja I Bork
- Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Germany (N.I.B., V.O.N.)
| | - Julia Straubinger
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, Germany (S.F., A.K., J.S., E.M., P.R., R.L.)
| | - Piotr Koprowski
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Warsaw, Poland (P.K., A.W., A.S.)
| | - Antoni Wrzosek
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Warsaw, Poland (P.K., A.W., A.S.)
| | - Eva Mohr
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, Germany (S.F., A.K., J.S., E.M., P.R., R.L.)
| | | | | | - Meinrad Gawaz
- University of Cambridge, Cambridge Biomedical Campus, United Kingdom. Internal Medicine III, Cardiology and Cardiovascular Medicine, University Hospital Tuebingen, Germany (M.G.)
| | | | - Adam Szewczyk
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Warsaw, Poland (P.K., A.W., A.S.)
| | - Viacheslav O Nikolaev
- Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Germany (N.I.B., V.O.N.)
| | - Peter Ruth
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, Germany (S.F., A.K., J.S., E.M., P.R., R.L.)
| | - Robert Lukowski
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, Germany (S.F., A.K., J.S., E.M., P.R., R.L.)
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25
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Lishmanov YB, Naryzhnaya NV, Tsibul’nikov SY, Wang H, Maslov LN. Role of ATP-Sensitive K+ Channels in Myocardial Infarct Size-Limiting Effect of Chronic Continuous Normobaric Hypoxia. Bull Exp Biol Med 2017; 163:22-24. [DOI: 10.1007/s10517-017-3728-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Indexed: 11/25/2022]
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26
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Zhang Y, Chen Z, Feng N, Tang J, Zhao X, Liu C, Xu H, Zhang M. Protective effect of propofol preconditioning on ischemia-reperfusion injury in human hepatocyte. J Thorac Dis 2017; 9:702-710. [PMID: 28449478 DOI: 10.21037/jtd.2017.02.80] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Blood reperfusion after ischemia is the main measure to restore cell function. This study was aimed to explore the effect of propofol on rat and cell models of liver ischemia-reperfusion (I/R) injury, and to investigate its possible mechanism. METHODS Wistar rats were divided into four groups: control group, sham group, I/R group, and propofol group. Human hepatocyte HL7702 was divided into six groups: control group, I/R group and propofol (5, 10, 20 and 40 µmol/L) groups. After the animal and cell models were established, the alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA) and adenosine triphosphate (ATP) levels in liver tissues and hepatocytes were measured. Cell viability and apoptosis of hepatocytes were respectively determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and flow cytometry. Furthermore, the expressions of apoptosis-related proteins in hepatocytes were determined by Western blot analysis. RESULTS ALT, AST and MDA levels were all decreased significantly, and the ATP level was increased significantly in propofol group compared with that in I/R group in both liver tissues and hepatocytes. Additionally, cell viability of hepatocytes in propofol group was higher than that in I/R group, while the percentage of apoptotic cells in propofol group was less than that in I/R group. Moreover, the expression of caspase-3 decreased and the expression of Bcl-2 increased significantly after propofol preconditioning. CONCLUSIONS Our findings suggested that propofol preconditioning might be an effective strategy for protecting the liver from I/R injury, which might provide a scientific basis for clinical application.
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Affiliation(s)
- Yuzhu Zhang
- Department of Anesthesiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China.,Department of Anesthesiology, Zibo Central Hospital, Zibo 255000, China
| | - Zhenzhen Chen
- Department of Anesthesiology, Zibo Central Hospital, Zibo 255000, China
| | - Nianhai Feng
- Department of Anesthesiology, Zibo Central Hospital, Zibo 255000, China
| | - Junxia Tang
- Department of Anesthesiology, Zibo Central Hospital, Zibo 255000, China
| | - Xingbo Zhao
- Department of Gynaecology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China
| | - Chengxiao Liu
- Department of Anesthesiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China
| | - Hongyu Xu
- Department of Anesthesiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China.,Department of Anesthesiology, Zibo Central Hospital, Zibo 255000, China
| | - Mengyuan Zhang
- Department of Anesthesiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China
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27
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Lindberg U, Witting N, Jørgensen SL, Vissing J, Rostrup E, Larsson HBW, Kruuse C. Effects of Sildenafil on Cerebrovascular Reactivity in Patients with Becker Muscular Dystrophy. Neurotherapeutics 2017; 14:182-190. [PMID: 27485237 PMCID: PMC5233618 DOI: 10.1007/s13311-016-0467-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Patients suffering from Becker muscular dystrophy (BMD) have dysfunctional dystrophin proteins and are deficient in neuronal nitric oxide synthase (nNOS) in muscles. This causes functional ischemia and contributes to muscle wasting. Similar functional ischemia may be present in brains of patients with BMD, who often have mild cognitive impairment, and nNOS may be important for the regulation of the microvascular circulation in the brain. We hypothesized that treatment with sildenafil, a phosphodiesterase type 5 inhibitor that potentiates nitric oxide responses, would augment both the blood oxygen level-dependent (BOLD) response and cerebral blood flow (CBF) in patients with BMD. Seventeen patients (mean ± SD age 38.5 ± 10.8 years) with BMD were included in this randomized, double-blind, placebo-controlled, crossover trial. Twelve patients completed the entire study. Effects of sildenafil were assessed by 3 T magnetic resonance (MR) scanning, evoked potentials, somatosensory task-induced BOLD functional MR imaging, regional and global perfusion, and angiography before and after 4 weeks of sildenafil, 20 mg (Revatio in gelatine capsules, oral, 3 times daily), or placebo treatment. Sildenafil increased the event-related sensory and visual BOLD response compared with placebo (p < 0.01). However, sildenafil did not alter CBF, measured by MR phase contrast mapping, or the arterial diameter of the middle cerebral artery, measured by MR angiography. We conclude that nNOS may play a role in event-related neurovascular responses. Further studies in patients with BMD may help clarify the roles of dystrophin and nNOS in neurovascular coupling in general, and in patients with BMD in particular.
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Affiliation(s)
- Ulrich Lindberg
- Functional Imaging Unit, Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet Glostrup, University of Copenhagen, Glostrup, Denmark
- Lundbeck Foundation Center for Neurovascular signalling (LUCENS), Rigshospitalet Glostrup, University of Copenhagen, Glostrup, Denmark
| | - Nanna Witting
- Copenhagen Neuromuscular Center and Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Stine Lundgaard Jørgensen
- Lundbeck Foundation Center for Neurovascular signalling (LUCENS), Rigshospitalet Glostrup, University of Copenhagen, Glostrup, Denmark
| | - John Vissing
- Copenhagen Neuromuscular Center and Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Egill Rostrup
- Functional Imaging Unit, Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet Glostrup, University of Copenhagen, Glostrup, Denmark
| | - Henrik Bo Wiberg Larsson
- Functional Imaging Unit, Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet Glostrup, University of Copenhagen, Glostrup, Denmark
- Lundbeck Foundation Center for Neurovascular signalling (LUCENS), Rigshospitalet Glostrup, University of Copenhagen, Glostrup, Denmark
| | - Christina Kruuse
- Lundbeck Foundation Center for Neurovascular signalling (LUCENS), Rigshospitalet Glostrup, University of Copenhagen, Glostrup, Denmark.
- Neurovascular Research Unit, Department of Neurology, Herlev Gentofte Hospital, University of Copenhagen, Herlev, Denmark.
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Abstract
Cardiac arrhythmias can follow disruption of the normal cellular electrophysiological processes underlying excitable activity and their tissue propagation as coherent wavefronts from the primary sinoatrial node pacemaker, through the atria, conducting structures and ventricular myocardium. These physiological events are driven by interacting, voltage-dependent, processes of activation, inactivation, and recovery in the ion channels present in cardiomyocyte membranes. Generation and conduction of these events are further modulated by intracellular Ca2+ homeostasis, and metabolic and structural change. This review describes experimental studies on murine models for known clinical arrhythmic conditions in which these mechanisms were modified by genetic, physiological, or pharmacological manipulation. These exemplars yielded molecular, physiological, and structural phenotypes often directly translatable to their corresponding clinical conditions, which could be investigated at the molecular, cellular, tissue, organ, and whole animal levels. Arrhythmogenesis could be explored during normal pacing activity, regular stimulation, following imposed extra-stimuli, or during progressively incremented steady pacing frequencies. Arrhythmic substrate was identified with temporal and spatial functional heterogeneities predisposing to reentrant excitation phenomena. These could arise from abnormalities in cardiac pacing function, tissue electrical connectivity, and cellular excitation and recovery. Triggering events during or following recovery from action potential excitation could thereby lead to sustained arrhythmia. These surface membrane processes were modified by alterations in cellular Ca2+ homeostasis and energetics, as well as cellular and tissue structural change. Study of murine systems thus offers major insights into both our understanding of normal cardiac activity and its propagation, and their relationship to mechanisms generating clinical arrhythmias.
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Affiliation(s)
- Christopher L-H Huang
- Physiological Laboratory and the Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
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29
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Li L, Hou X, Xu R, Liu C, Tu M. Research review on the pharmacological effects of astragaloside IV. Fundam Clin Pharmacol 2016; 31:17-36. [PMID: 27567103 DOI: 10.1111/fcp.12232] [Citation(s) in RCA: 240] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Revised: 07/09/2016] [Accepted: 08/26/2016] [Indexed: 12/11/2022]
Abstract
Astragalus membranaceus Bunge has been used to treat numerous diseases for thousands of years. As the main active substance of Astragalus membranaceus Bunge, astragaloside IV (AS-IV) also demonstrates the potent protective effect on focal cerebral ischemia/reperfusion, cardiovascular disease, pulmonary disease, liver fibrosis, and diabetic nephropathy. Based on studies published during the past several decades, the current state of AS-IV research and the pharmacological effects are detailed, elucidated, and summarized. This review systematically summarizes the pharmacological effects, metabolism mechanism, and the toxicity of AS-IV. AS-IV has multiple pharmacologic effects, including anti-inflammatory, antifibrotic, antioxidative stress, anti-asthma, antidiabetes, immunoregulation, and cardioprotective effect via numerous signaling pathways. According to the existing studies and clinical practices, AS-IV possesses potential for broad application in many diseases.
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Affiliation(s)
- Lei Li
- College of Animal Science, Anhui Science and Technology University, Chuzhou, China
| | - Xiaojiao Hou
- Engineering Research Center of Chinese Traditional Veterinary Medicine, Beijing, China
| | - Rongfang Xu
- Engineering Research Center of Chinese Traditional Veterinary Medicine, Beijing, China
| | - Chang Liu
- College of Animal Science, Anhui Science and Technology University, Chuzhou, China
| | - Menbayaer Tu
- Engineering Research Center of Chinese Traditional Veterinary Medicine, Beijing, China
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30
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Yoshioka K, Otani H, Shimazu T, Fujita M, Iwasaka T, Shiojima I. Sepiapterin prevents left ventricular hypertrophy and dilatory remodeling induced by pressure overload in rats. Am J Physiol Heart Circ Physiol 2015; 309:H1782-91. [PMID: 26408540 DOI: 10.1152/ajpheart.00417.2015] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Accepted: 09/22/2015] [Indexed: 01/01/2023]
Abstract
Uncoupling of nitric oxide (NO) synthase (NOS) has been implicated in left ventricular (LV) hypertrophy (LVH) and dilatory remodeling induced by pressure overload. We investigated whether administration of sepiapterin, a substrate of the salvage pathway of tetrahydrobiopterin synthesis, prevents LVH and dilatory LV remodeling by inhibiting NOS uncoupling and increasing bioavailable NO. Pressure overload was induced in rats by transverse aortic constriction (TAC). Concentric LVH developed during 8 wk after TAC, and dilatory LV remodeling and dysfunction developed between 8 and 16 wk after TAC associated with a decrease in capillary density. Oral administration of sepiapterin or the superoxide/peroxynitrite scavenger N-(2-mercaptopropionyl)-glycine for 8 wk after TAC inhibited oxidative stress, but only sepiapterin increased bioavailable NO and inhibited cardiomyocyte hypertrophy associated with a further increase in capillary density. When sepiapterin was administered between 8 and 16 wk after TAC, cardiomyocyte hypertrophy was regressed and capillary density was restored. This was associated with the inhibition of interstitial fibrosis and dilatory LV remodeling. N-nitro-l-arginine methyl ester abrogated all the beneficial effects of sepiapterin in rats with TAC. These results suggest that sepiapterin prevents concentric LVH and dilatory remodeling after TAC primarily by increasing the bioavailability of NO.
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MESH Headings
- Animals
- Aorta/surgery
- Biopterins/analogs & derivatives
- Biopterins/biosynthesis
- Capillaries/pathology
- Cell Size
- Constriction
- Dilatation, Pathologic/diagnostic imaging
- Dilatation, Pathologic/metabolism
- Enzyme Inhibitors/pharmacology
- Glycine/analogs & derivatives
- Glycine/pharmacology
- Heart/drug effects
- Hypertrophy, Left Ventricular/diagnostic imaging
- Hypertrophy, Left Ventricular/metabolism
- Hypertrophy, Left Ventricular/pathology
- Male
- Myocardium/metabolism
- Myocardium/pathology
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- NG-Nitroarginine Methyl Ester/pharmacology
- Nitric Oxide/metabolism
- Nitric Oxide Synthase/drug effects
- Nitric Oxide Synthase/metabolism
- Organ Size
- Oxidative Stress/drug effects
- Pressure
- Pterins/pharmacology
- Rats
- Rats, Sprague-Dawley
- Sulfhydryl Compounds/pharmacology
- Ultrasonography
- Ventricular Dysfunction, Left/diagnostic imaging
- Ventricular Dysfunction, Left/metabolism
- Ventricular Dysfunction, Left/pathology
- Ventricular Remodeling/drug effects
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Affiliation(s)
- Kei Yoshioka
- Department of Internal Medicine II, Kansai Medical University, Moriguchi City, Japan
| | - Hajime Otani
- Department of Internal Medicine II, Kansai Medical University, Moriguchi City, Japan
| | - Takayuki Shimazu
- Department of Internal Medicine II, Kansai Medical University, Moriguchi City, Japan
| | - Masanori Fujita
- Department of Internal Medicine II, Kansai Medical University, Moriguchi City, Japan
| | - Toshiji Iwasaka
- Department of Internal Medicine II, Kansai Medical University, Moriguchi City, Japan
| | - Ichiro Shiojima
- Department of Internal Medicine II, Kansai Medical University, Moriguchi City, Japan
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31
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Scutellarin's Cardiovascular Endothelium Protective Mechanism: Important Role of PKG-Iα. PLoS One 2015; 10:e0139570. [PMID: 26440524 PMCID: PMC4594915 DOI: 10.1371/journal.pone.0139570] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Accepted: 09/15/2015] [Indexed: 11/21/2022] Open
Abstract
Scutellarin (SCU), a flavonoid glycoside compound, has been successfully used in clinic for treatment of ischemic diseases in China. In this report, we checked the effects of SCU on endothelium dysfunction (ED) of coronary artery (CA) against myocardial ischemia reperfusion (MIR) injury in vivo. The involvement of PKG-Iα was further studied using cultured endothelial cells subjected to hypoxia reoxygenation (HR) injury in vitro. In rat MIR model, SCU (45 and 90 mg/kg, iv) significantly reduced ischemic size and restored the endothelium-dependent vasodilation of isolated CA rings. PKG inhibitor Rp-8-Br-cGMP (50 μg/kg, iv) could ameliorate the protective effects of SCU. Increase in phosphorylation of vasodilator-stimulated phosphoprotein (VASP), a main substrate of PKG, at Ser 239 was observed in both heart tissue and serum of SCU-treated animals. In cultured human cardiac microvascular endothelial cells (HCMECs), SCU (1 and 10 μM) dose-dependently protected cell viability and increased the mRNA and protein level of PKG-Iα against HR injury. The activity of PKG was also increased by SCU treatment. The activation of PKG–1α was then studied using targeted proteomic analysis (MRM-MS) checking the phosphorylation state of the autophosphorylation domain (aa42-94). Significant decrease in phosphorylation of PKG-Iα at Ser50, Ser72, Ser89 was induced by HR injury while SCU treatment significantly increased the phosphorylation of PKG-Iα, not only at Ser50, Ser72 and Ser89, but also at Ser44 and Thr58 (two novel phosphorylation domains). Our results demonstrate PKG-Iα might play an important role in the protective effects of SCU on ED against MIR injury.
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Li W, Wu N, Shu W, Jia D, Jia P. Pharmacological preconditioning and postconditioning with nicorandil attenuates ischemia/reperfusion-induced myocardial necrosis and apoptosis in hypercholesterolemic rats. Exp Ther Med 2015; 10:2197-2205. [PMID: 26668616 DOI: 10.3892/etm.2015.2782] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Accepted: 09/01/2015] [Indexed: 12/13/2022] Open
Abstract
Pharmacological preconditioning and postconditioning may reduce myocardial necrosis and apoptosis during ischemia/reperfusion (I/R), however, hypercholesterolemia interferes with the associated cardioprotective mechanisms. The present study investigated whether pharmacological preconditioning and postconditioning with nicorandil could attenuate myocardial necrosis and apoptosis induced by I/R in hypercholesterolemic rats, and explored the possible mechanisms involved. Male Wistar rats (n=160) were fed normal (normocholesterolemic group, n=10) or high-cholesterol (hypercholesterolemic group, n=150) diets for 8 weeks. Hearts harvested from the normal and hypercholesterolemic rats were subsequently placed on modified Langendorff perfusion apparatus and 30-min global ischemia was performed, followed by 120-min reperfusion. Nicorandil (1, 3, 10, 30, 100 µmol/l), and mitochondrial adenosine triphosphate-sensitive potassium (mitoKATP) channel blocker 5-hydroxydecanoic acid sodium salt (5-HD) (100 µmol/l) or soluble guanylyl cyclase (sGC) blocker 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 µmol/l) were perfused for 10 min, prior to ischemia or at the onset of reperfusion. The myocardial infarct size was determined by triphenyltetrazolium chloride staining, and cardiomyocyte apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick-end labeling staining. In order to investigate the potential mechanisms, the expression levels of caspase-3, B-cell lymphoma-2 (Bcl-2) proteins and Bcl-2-associated X protein (Bax) were measured using western blot analysis. The present study demonstrated that, in hypercholesterolemic rats, pharmacological preconditioning and postconditioning with nicorandil decreased I/R-induced myocardial necrosis and apoptosis in a concentration-dependent manner. The optimal preconditioning and postconditioning concentration of nicorandil determined to have anti-infarct and anti-apoptosis effects was 30 µmol/l, which significantly (P<0.05) reduced the infarct size to 14.88±3.25% and 15.96±3.29%, and attenuated the percentage of cardiomyocyte apoptosis to 25.20±3.93% and 26.18±4.82%, respectively, compared with the I/R group. However, the cardioprotective effects of nicorandil were partially suppressed by cotreatment with 5-HD or ODQ. Western blot analysis demonstrated that pharmacological preconditioning and postconditioning with nicorandil significantly downregulated caspase-3 and Bax expression, and upregulated Bcl-2 expression compared with the I/R group (P<0.05). The results of the present study suggest that pharmacological preconditioning and postconditioning with nicorandil may protect hypercholesterolemic hearts against I/R-induced necrosis and apoptosis; and the cardioprotective effects of nicorandil may be due to the dual pharmacological mechanisms of opening the mitoKATP channels and a nitric oxide/sGC-dependent mechanism, and regulation of the expression of caspase-3, Bax and Bcl-2.
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Affiliation(s)
- Wenna Li
- Department of Cardiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Nan Wu
- Department of Cardiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Wenqi Shu
- Department of Cardiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Dalin Jia
- Department of Cardiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Pengyu Jia
- Department of Cardiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
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Zhong Z, Ye S, Xiong Y, Wu L, Zhang M, Fan X, Li L, Fu Z, Wang H, Chen M, Yan X, Huang W, Ko DSC, Wang Y, Ye Q. Decreased expression of mitochondrial aldehyde dehydrogenase-2 induces liver injury via activation of the mitogen-activated protein kinase pathway. Transpl Int 2015; 29:98-107. [PMID: 26404764 DOI: 10.1111/tri.12675] [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: 02/12/2015] [Revised: 03/31/2015] [Accepted: 08/20/2015] [Indexed: 12/18/2022]
Abstract
The aim of this study was to determine the role of ALDH2 in the injury of liver from brain-dead donors. Using brain-dead rabbit model and hypoxia model, levels of ALDH2 and apoptosis in tissues and cell lines were determined by Western blot, flow cytometry (FCM), and transferase (TdT)-mediated biotin-16-dUTP nick-end labeling (TUNEL) assays. After the expression of ALDH2 during hypoxia had been inhibited or activated, the accumulations of 4-hydroxynonenal (4-HNE) and molecules involved in mitogen-activated protein kinase (MAPK) signaling pathway were analyzed using ELISA kit and Western blot. The low expression of phosphorylated ALDH2 in liver was time-dependent in the brain-dead rabbit model. Immunohistochemistry showed ALDH2 was primarily located in endothelial, and the rates of cell apoptosis in the donation after brain-death (DBD) rabbit groups significantly increased with time. Following the treatment of inhibitor of ALDH2, daidzein, in combination with hypoxia for 8 h, the apoptosis rate and the levels of 4-HNE, P-JNK, and cleaved caspase-3 significantly increased in contrast to that in hypoxic HUVECs; however, they all decreased after treatment with Alda-1 and hypoxia compared with that in hypoxic HUVECs (P < 0.05). Instead, the levels of P-P38, P-ERK, P-JNK, and cleaved caspase-3 decreased and the ratio of bcl-2/bax increased with ad-ALDH2 (10(6) pfu/ml) in combination with hypoxia for 8 h, which significantly alleviated in contrast to that in hypoxic HUVECs. We found low expression of ALDH2 and high rates of apoptosis in the livers of brain-dead donor rabbits. Furthermore, decreased ALDH2 led to apoptosis in HUVECs through MAPK pathway.
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Affiliation(s)
- Zibiao Zhong
- Wuhan University, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan Hubei, China
| | - Shaojun Ye
- Wuhan University, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan Hubei, China
| | - Yan Xiong
- Wuhan University, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan Hubei, China
| | - Lianxi Wu
- Jianghan District Center for Disease Control and Prevention, Wuhan Hubei, China
| | - Meng Zhang
- Wuhan University, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan Hubei, China
| | - Xiaoli Fan
- Wuhan University, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan Hubei, China
| | - Ling Li
- Wuhan University, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan Hubei, China
| | - Zhen Fu
- The 3rd Xiangya Hospital of Central South University, Research Center of National Health Ministry on Transplantation Medicine Engineering and Technology, Changsha, China
| | - Huanglei Wang
- Wuhan University, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan Hubei, China
| | - Mingyun Chen
- Wuhan University, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan Hubei, China
| | - Xiaomin Yan
- Wuhan University, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan Hubei, China
| | - Wei Huang
- Wuhan University, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan Hubei, China
| | - Dicken Shiu-Chung Ko
- Massachusetts General Hospital, Department of Urology, Harvard Medical School, Boston, MA, USA
| | - Yanfeng Wang
- Wuhan University, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan Hubei, China
| | - Qifa Ye
- Wuhan University, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan Hubei, China.,The 3rd Xiangya Hospital of Central South University, Research Center of National Health Ministry on Transplantation Medicine Engineering and Technology, Changsha, China
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Correa F, Buelna-Chontal M, Chagoya V, García-Rivas G, Vigueras RM, Pedraza-Chaverri J, García-Niño WR, Hernández-Pando R, León-Contreras JC, Zazueta C. Inhibition of the nitric oxide/cyclic guanosine monophosphate pathway limited the cardioprotective effect of post-conditioning in hearts with apical myocardial infarction. Eur J Pharmacol 2015; 765:472-81. [PMID: 26387613 DOI: 10.1016/j.ejphar.2015.09.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Revised: 09/09/2015] [Accepted: 09/14/2015] [Indexed: 11/19/2022]
Abstract
Reperfusion damage involves opening of the mitochondrial permeability transition pore (mPTP) and loss of ATP synthesis. Several cardioprotective pathways are activated by ischemic or pharmacological post-conditioning (PC). The mechanisms that are activated by PC in no co-morbidity murine models include: activation of rescue kinases, oxidative stress reduction, glycolytic flux regulation and preservation of ATP synthesis. However, relatively scarce efforts have been made to define whether the efficacy of PC signaling is blunted by risk factors or systemic diseases associated with ischemic heart pathology. Experimental evidence has shown that the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling is a main mechanism activated by PC in hearts without pathological history. In this work we evaluated the participation of the NO pathway, through downstream kinase activation and inhibition of mPTP in hearts with previous infarct. Myocardial infarction was induced with a single dose of isoproterenol (85 mg/kg i.p.) to male Wistar rats. After 24 h, the hearts were mounted into the Langendorff system and subjected to 30 min of ischemia and 60 min of reperfusion. PC consisted of 5 cycles of 30 s of reperfusion/30 s of ischemia, then the hearts were reperfused with or without inhibitors of the NO/cGMP pathway. PC activates the NO/cGMP pathway, as increased cGMP and NO levels were detected in isoproterenol-treated hearts. The cardioprotective effect of PC was abolished with both L-NAME (inhibitor of constitutive NO synthase) and ODQ (inhibitor of soluble guanylate cyclase), whereas the NO donor (DETA-NO) restored cardioprotection even in the presence of L-NAME or ODQ. We also found that mitochondrial structure and function was preserved in PC hearts. We conclude that PC exerts cardioprotection in hearts with previous infarct by maintaining mitochondrial structure and function through NO-dependent pathway.
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Affiliation(s)
- Francisco Correa
- Departamento de Biomedicina Cardiovascular, Instituto Nacional de Cardiología, I. Ch., Juan Badiano No. 1., Col. Sección XVI, México D.F. 14080, Mexico.
| | - Mabel Buelna-Chontal
- Departamento de Biomedicina Cardiovascular, Instituto Nacional de Cardiología, I. Ch., Juan Badiano No. 1., Col. Sección XVI, México D.F. 14080, Mexico
| | - Victoria Chagoya
- Departamento de Biología Celular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México, D.F., Mexico
| | - Gerardo García-Rivas
- Centro de Innovación y Transferencia en Salud de la Escuela de Medicina del Tecnológico de Monterrey, Cátedra de Cardiología y Medicina Vascular, Instituto de Cardiología y Medicina Vascular del Tecnológico de Monterrey, Monterrey, N.L. 64710, Mexico
| | - Rosa María Vigueras
- Laboratorio de Histomorfología, Torre de Investigación, Instituto Nacional de Pediatría, SS, México D.F. 04530, Mexico
| | - José Pedraza-Chaverri
- Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, 04510 México DF, Mexico
| | - Wylly Ramsés García-Niño
- Departamento de Biomedicina Cardiovascular, Instituto Nacional de Cardiología, I. Ch., Juan Badiano No. 1., Col. Sección XVI, México D.F. 14080, Mexico
| | - Rogelio Hernández-Pando
- Sección de Patología Experimental, Departamento de Patología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Av. Vasco De Quiroga 15, Tlalpan, México D.F., Mexico
| | - Juan Carlos León-Contreras
- Sección de Patología Experimental, Departamento de Patología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Av. Vasco De Quiroga 15, Tlalpan, México D.F., Mexico
| | - Cecilia Zazueta
- Departamento de Biomedicina Cardiovascular, Instituto Nacional de Cardiología, I. Ch., Juan Badiano No. 1., Col. Sección XVI, México D.F. 14080, Mexico
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Heusch G. Treatment of Myocardial Ischemia/Reperfusion Injury by Ischemic and Pharmacological Postconditioning. Compr Physiol 2015; 5:1123-1145. [PMID: 26140711 DOI: 10.1002/cphy.c140075] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Timely reperfusion is the only way to salvage ischemic myocardium from impending infarction. However, reperfusion also adds a further component to myocardial injury such that the ultimate infarct size is the result of both ischemia- and reperfusion-induced injury. Modification of reperfusion can attenuate reperfusion injury and thus reduce infarct size. Ischemic postconditioning is a maneuver of repeated brief interruption of reperfusion by short-lasting coronary occlusions which results in reduced infarct size. Cardioprotection by ischemic postconditioning is mediated through delayed reversal of acidosis and the activation of a complex signal transduction cascade, including triggers such as adenosine, bradykinin, and opioids, mediators such as protein kinases and, notably, mitochondrial function as effector. Inhibition of the mitochondrial permeability transition pore appears to be a final signaling step of ischemic postconditioning. Several drugs which recruit in part such signaling steps of ischemic postconditioning can induce cardioprotection, even when the drug is only administered at reperfusion, that is, there is also pharmacological postconditioning. Ischemic and pharmacological postconditioning have been translated to patients with acute myocardial infarction in proof-of-concept studies, but further mechanistic insight is needed to optimize the conditions and algorithms of cardioprotection by postconditioning.
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Affiliation(s)
- Gerd Heusch
- Institut für Pathophysiologie, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany
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Martin-Puig S, Tello D, Aragonés J. Novel perspectives on the PHD-HIF oxygen sensing pathway in cardioprotection mediated by IPC and RIPC. Front Physiol 2015; 6:137. [PMID: 26042040 PMCID: PMC4438228 DOI: 10.3389/fphys.2015.00137] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Accepted: 04/17/2015] [Indexed: 12/31/2022] Open
Abstract
Reperfusion of ischemic cardiac tissue is the standard treatment for improving clinical outcome following myocardial infarction but is inevitably associated with ischemia-reperfusion injury (IRI). Ischemic myocardial injury can be alleviated by exposing the heart to brief episodes of sublethal ischemia-reperfusion prior to the ischemic insult, a phenomenon that has been termed ischemic preconditioning (IPC). Similarly, remote IPC (RIPC) is defined as transient episodes of ischemia at a distant site before a subsequent prolonged injury of the target organ. In this setting, adaptive responses to hypoxia/ischemia in peripheral tissues include the release of soluble factors that have the potential to protect cardiomyocytes remotely. Oxygen fluctuations is a hallmark of insufficient tissue perfusion and ischemic episodes. Emerging evidence indicates that prolyl hydroxylase oxygen sensors (PHDs) and hypoxia-inducible transcription factors (HIFs) are critical regulators of IPC and RIPC. In this review, we discuss recent findings concerning the role of the PHD-HIF axis in IPC and RIPC-mediated cardioprotection and examine molecular pathways and cell types that might be involved. We also appraise the therapeutic value of targeting the PHD-HIF axis to enhance cardiac tolerance against IRI.
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Affiliation(s)
- Silvia Martin-Puig
- Cell and Developmental Biology Department, Centro Nacional de Investigaciones Cardiovasculares Madrid, Spain
| | - Daniel Tello
- Research Unit, Hospital Santa Cristina, Research Institute Princesa (IP), Autonomous University of Madrid Madrid, Spain
| | - Julián Aragonés
- Research Unit, Hospital Santa Cristina, Research Institute Princesa (IP), Autonomous University of Madrid Madrid, Spain
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Abstract
Reperfusion is mandatory to salvage ischemic myocardium from infarction, but reperfusion per se contributes to injury and ultimate infarct size. Therefore, cardioprotection beyond that by timely reperfusion is needed to reduce infarct size and improve the prognosis of patients with acute myocardial infarction. The conditioning phenomena provide such cardioprotection, insofar as brief episodes of coronary occlusion/reperfusion preceding (ischemic preconditioning) or following (ischemic postconditioning) sustained myocardial ischemia with reperfusion reduce infarct size. Even ischemia/reperfusion in organs remote from the heart provides cardioprotection (remote ischemic conditioning). The present review characterizes the signal transduction underlying the conditioning phenomena, including their physical and chemical triggers, intracellular signal transduction, and effector mechanisms, notably in the mitochondria. Cardioprotective signal transduction appears as a highly concerted spatiotemporal program. Although the translation of ischemic postconditioning and remote ischemic conditioning protocols to patients with acute myocardial infarction has been fairly successful, the pharmacological recruitment of cardioprotective signaling has been largely disappointing to date.
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Affiliation(s)
- Gerd Heusch
- From the Institute for Pathophysiology, West German Heart and Vascular Centre, University of Essen Medical School, Essen, Germany.
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Cohen MV, Downey JM. Signalling pathways and mechanisms of protection in pre- and postconditioning: historical perspective and lessons for the future. Br J Pharmacol 2015; 172:1913-32. [PMID: 25205071 PMCID: PMC4386972 DOI: 10.1111/bph.12903] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Revised: 08/22/2014] [Accepted: 08/29/2014] [Indexed: 12/19/2022] Open
Abstract
Ischaemic pre- and postconditioning are potent cardioprotective interventions that spare ischaemic myocardium and decrease infarct size after periods of myocardial ischaemia/reperfusion. They are dependent on complex signalling pathways involving ligands released from ischaemic myocardium, G-protein-linked receptors, membrane growth factor receptors, phospholipids, signalling kinases, NO, PKC and PKG, mitochondrial ATP-sensitive potassium channels, reactive oxygen species, TNF-α and sphingosine-1-phosphate. The final effector is probably the mitochondrial permeability transition pore and the signalling produces protection by preventing pore formation. Many investigators have worked to produce a roadmap of this signalling with the hope that it would reveal where one could intervene to therapeutically protect patients with acute myocardial infarction whose hearts are being reperfused. However, attempts to date to show efficacy of such an intervention in large clinical trials have been unsuccessful. Reasons for this inability to translate successes in the experimental laboratory to the clinical arena are evaluated in this review. It is suggested that all patients with acute coronary syndromes currently presenting to the hospital and being treated with platelet P2Y12 receptor antagonists, the current standard of care, are indeed already benefiting from protection from the conditioning pathways outlined earlier. If that proves to be the case, then future attempts to further decrease infarction will have to rely on interventions which protect by a different mechanism.
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Affiliation(s)
- Michael V Cohen
- Department of Physiology, University of South Alabama College of MedicineMobile, AL, USA
- Department of Medicine, University of South Alabama College of MedicineMobile, AL, USA
| | - James M Downey
- Department of Physiology, University of South Alabama College of MedicineMobile, AL, USA
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Ozawa T, Shinke T, Shite J, Takaoka H, Inoue N, Matsumoto H, Watanabe S, Yoshikawa R, Otake H, Matsumoto D, Ogasawara D, Yokoyama M, Hirata KI. Effects of human atrial natriuretic peptide on myocardial performance and energetics in heart failure due to previous myocardial infarction. J Cardiol 2015; 66:232-8. [PMID: 25722046 DOI: 10.1016/j.jjcc.2014.12.020] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2014] [Revised: 12/06/2014] [Accepted: 12/28/2014] [Indexed: 11/16/2022]
Abstract
BACKGROUND Human atrial natriuretic peptide (hANP) and spontaneous nitric oxide (NO) donor share cyclic guanosine monophosphate (cGMP) as a second messenger, but their effect on myocardium may differ. We compared the effect of hANP and sodium nitroprusside (SNP) on left ventricular (LV) mechano-energetics in heart failure (HF). METHODS Ten patients with HF due to previous myocardial infarction (LV ejection fraction: 45±3%) were instrumented with conductance and coronary sinus thermodilution catheters. LV contractility (Ees: slope of end-systolic pressure-volume relation) and the ratio of LV stroke work (SW) to myocardial oxygen consumption (SW/MVO2=mechanical efficiency) were measured in response to intravenous infusion of ANP (0.05 μg/kg/min) or SNP (0.3 μg/kg/min) to lower blood pressure by at least 10 mmHg, and changes in plasma cGMP. RESULTS SNP had no effect on Ees, SW, or MVO2, thus SW/MVO2 remained unchanged (40.54±5.84% to 36.59±5.72%, p=0.25). ANP increased Ees, and decreased MVO2 with preserved SW, resulting in improved SW/MVO2 (40.49±6.35% to 50.30±7.96%, p=0.0073). Infusion of ANP (10.42-34.95 pmol/ml, p=0.0003) increased cGMP levels, whereas infusion of SNP had no effect (10.42-12.23 pmol/ml, p=0.75). CONCLUSIONS Compared to SNP, the ANP-dependent increase in cGMP may ameliorate myocardial inotropy and energetics in HF.
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Affiliation(s)
- Toru Ozawa
- Kobe Rosai Hospital, Department of Cardiology, Kobe, Japan
| | - Toshiro Shinke
- Kobe University Graduate School of Medicine, Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe, Japan.
| | - Junya Shite
- Kobe University Graduate School of Medicine, Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe, Japan
| | - Hideyuki Takaoka
- Kobe University Graduate School of Medicine, Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe, Japan
| | - Nobutaka Inoue
- Kobe Rosai Hospital, Department of Cardiology, Kobe, Japan
| | - Hidenari Matsumoto
- Kobe University Graduate School of Medicine, Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe, Japan
| | - Satoshi Watanabe
- Kobe University Graduate School of Medicine, Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe, Japan
| | - Ryohei Yoshikawa
- Kobe University Graduate School of Medicine, Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe, Japan
| | - Hiromasa Otake
- Kobe University Graduate School of Medicine, Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe, Japan
| | - Daisuke Matsumoto
- Kobe University Graduate School of Medicine, Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe, Japan
| | - Daisuke Ogasawara
- Kobe University Graduate School of Medicine, Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe, Japan
| | - Mitsuhiro Yokoyama
- Kobe University Graduate School of Medicine, Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe, Japan
| | - Ken-ichi Hirata
- Kobe University Graduate School of Medicine, Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe, Japan
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Role of phosphoinositide 3-kinase IA (PI3K-IA) activation in cardioprotection induced by ouabain preconditioning. J Mol Cell Cardiol 2015; 80:114-25. [PMID: 25575882 DOI: 10.1016/j.yjmcc.2014.12.021] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2014] [Revised: 12/06/2014] [Accepted: 12/26/2014] [Indexed: 11/23/2022]
Abstract
Acute myocardial infarction, the clinical manifestation of ischemia-reperfusion (IR) injury, is a leading cause of death worldwide. Like ischemic preconditioning (IPC) induced by brief episodes of ischemia and reperfusion, ouabain preconditioning (OPC) mediated by Na/K-ATPase signaling protects the heart against IR injury. Class I PI3K activation is required for IPC, but its role in OPC has not been investigated. While PI3K-IB is critical to IPC, studies have suggested that ouabain signaling is PI3K-IA-specific. Hence, a pharmacological approach was used to test the hypothesis that OPC and IPC rely on distinct PI3K-I isoforms. In Langendorff-perfused mouse hearts, OPC was initiated by 4 min of ouabain 10 μM and IPC was triggered by 4 cycles of 5 min ischemia and reperfusion prior to 40 min of global ischemia and 30 min of reperfusion. Without affecting PI3K-IB, ouabain doubled PI3K-IA activity and Akt phosphorylation at Ser(473). IPC and OPC significantly preserved cardiac contractile function and tissue viability as evidenced by left ventricular developed pressure and end-diastolic pressure recovery, reduced lactate dehydrogenase release, and decreased infarct size. OPC protection was blunted by the PI3K-IA inhibitor PI-103, but not by the PI3K-IB inhibitor AS-604850. In contrast, IPC-mediated protection was not affected by PI-103 but was blocked by AS-604850, suggesting that PI3K-IA activation is required for OPC while PI3K-IB activation is needed for IPC. Mechanistically, PI3K-IA activity is required for ouabain-induced Akt activation but not PKCε translocation. However, in contrast to PKCε translocation which is critical to protection, Akt activity was not required for OPC. Further studies shall reveal the identity of the downstream targets of this new PI3K IA-dependent branch of OPC. These findings may be of clinical relevance in patients at risk for myocardial infarction with underlying diseases and/or medication that could differentially affect the integrity of cardiac PI3K-IA and IB pathways.
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Karam BS, Akar FG. Blue LEDs get the Nobel Prize while Red LEDs are poised to save lives. Front Physiol 2014; 5:443. [PMID: 25452731 PMCID: PMC4231988 DOI: 10.3389/fphys.2014.00443] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 10/29/2014] [Indexed: 12/03/2022] Open
Affiliation(s)
- Basil S Karam
- The Cardiovascular Institute, Icahn School of Medicine at Mount Sinai New York, NY, USA
| | - Fadi G Akar
- The Cardiovascular Institute, Icahn School of Medicine at Mount Sinai New York, NY, USA
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42
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Soltysinska E, Bentzen BH, Barthmes M, Hattel H, Thrush AB, Harper ME, Qvortrup K, Larsen FJ, Schiffer TA, Losa-Reyna J, Straubinger J, Kniess A, Thomsen MB, Brüggemann A, Fenske S, Biel M, Ruth P, Wahl-Schott C, Boushel RC, Olesen SP, Lukowski R. KCNMA1 encoded cardiac BK channels afford protection against ischemia-reperfusion injury. PLoS One 2014; 9:e103402. [PMID: 25072914 PMCID: PMC4114839 DOI: 10.1371/journal.pone.0103402] [Citation(s) in RCA: 82] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Accepted: 07/01/2014] [Indexed: 12/18/2022] Open
Abstract
Mitochondrial potassium channels have been implicated in myocardial protection mediated through pre-/postconditioning. Compounds that open the Ca2+- and voltage-activated potassium channel of big-conductance (BK) have a pre-conditioning-like effect on survival of cardiomyocytes after ischemia/reperfusion injury. Recently, mitochondrial BK channels (mitoBKs) in cardiomyocytes were implicated as infarct-limiting factors that derive directly from the KCNMA1 gene encoding for canonical BKs usually present at the plasma membrane of cells. However, some studies challenged these cardio-protective roles of mitoBKs. Herein, we present electrophysiological evidence for paxilline- and NS11021-sensitive BK-mediated currents of 190 pS conductance in mitoplasts from wild-type but not BK-/- cardiomyocytes. Transmission electron microscopy of BK-/- ventricular muscles fibres showed normal ultra-structures and matrix dimension, but oxidative phosphorylation capacities at normoxia and upon re-oxygenation after anoxia were significantly attenuated in BK-/- permeabilized cardiomyocytes. In the absence of BK, post-anoxic reactive oxygen species (ROS) production from cardiomyocyte mitochondria was elevated indicating that mitoBK fine-tune the oxidative state at hypoxia and re-oxygenation. Because ROS and the capacity of the myocardium for oxidative metabolism are important determinants of cellular survival, we tested BK-/- hearts for their response in an ex-vivo model of ischemia/reperfusion (I/R) injury. Infarct areas, coronary flow and heart rates were not different between wild-type and BK-/- hearts upon I/R injury in the absence of ischemic pre-conditioning (IP), but differed upon IP. While the area of infarction comprised 28±3% of the area at risk in wild-type, it was increased to 58±5% in BK-/- hearts suggesting that BK mediates the beneficial effects of IP. These findings suggest that cardiac BK channels are important for proper oxidative energy supply of cardiomyocytes at normoxia and upon re-oxygenation after prolonged anoxia and that IP might indeed favor survival of the myocardium upon I/R injury in a BK-dependent mode stemming from both mitochondrial post-anoxic ROS modulation and non-mitochondrial localizations.
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MESH Headings
- Animals
- Cell Hypoxia
- Disease Models, Animal
- Energy Metabolism
- Indoles/pharmacology
- Ischemic Preconditioning
- Large-Conductance Calcium-Activated Potassium Channel alpha Subunits/genetics
- Large-Conductance Calcium-Activated Potassium Channel alpha Subunits/metabolism
- Large-Conductance Calcium-Activated Potassium Channels/chemistry
- Large-Conductance Calcium-Activated Potassium Channels/genetics
- Large-Conductance Calcium-Activated Potassium Channels/metabolism
- Membrane Potential, Mitochondrial/drug effects
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mitochondria, Heart/metabolism
- Muscle Fibers, Skeletal/ultrastructure
- Muscle, Skeletal/metabolism
- Myocardium/metabolism
- Myocytes, Cardiac/cytology
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/metabolism
- Oxidative Phosphorylation/drug effects
- Reactive Oxygen Species/metabolism
- Reperfusion Injury/metabolism
- Reperfusion Injury/pathology
- Tetrazoles/pharmacology
- Thiourea/analogs & derivatives
- Thiourea/pharmacology
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Affiliation(s)
- Ewa Soltysinska
- The Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Bo Hjorth Bentzen
- The Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark
| | - Maria Barthmes
- Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität, Munich, Germany; Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität, Munich, Germany
- Nanion Technologies GmbH, Munich, Germany
| | - Helle Hattel
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - A. Brianne Thrush
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Mary-Ellen Harper
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Klaus Qvortrup
- Department of Biomedical Sciences, Core Facility for Integrated Microscopy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip J. Larsen
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Tomas A. Schiffer
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Jose Losa-Reyna
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Julia Straubinger
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany
| | - Angelina Kniess
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany
| | - Morten Bækgaard Thomsen
- The Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Stefanie Fenske
- Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität, Munich, Germany; Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität, Munich, Germany
| | - Martin Biel
- Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität, Munich, Germany; Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität, Munich, Germany
| | - Peter Ruth
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany
| | - Christian Wahl-Schott
- Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität, Munich, Germany; Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität, Munich, Germany
| | - Robert Christopher Boushel
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Søren-Peter Olesen
- The Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- * E-mail: (SPO); (RL)
| | - Robert Lukowski
- Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany
- * E-mail: (SPO); (RL)
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43
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Kalogeris T, Bao Y, Korthuis RJ. Mitochondrial reactive oxygen species: a double edged sword in ischemia/reperfusion vs preconditioning. Redox Biol 2014; 2:702-14. [PMID: 24944913 PMCID: PMC4060303 DOI: 10.1016/j.redox.2014.05.006] [Citation(s) in RCA: 525] [Impact Index Per Article: 47.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Revised: 05/23/2014] [Accepted: 05/27/2014] [Indexed: 02/06/2023] Open
Abstract
Reductions in the blood supply produce considerable injury if the duration of ischemia is prolonged. Paradoxically, restoration of perfusion to ischemic organs can exacerbate tissue damage and extend the size of an evolving infarct. Being highly metabolic organs, the heart and brain are particularly vulnerable to the deleterious effects of ischemia/reperfusion (I/R). While the pathogenetic mechanisms contributing to I/R-induced tissue injury and infarction are multifactorial, the relative importance of each contributing factor remains unclear. However, an emerging body of evidence indicates that the generation of reactive oxygen species (ROS) by mitochondria plays a critical role in damaging cellular components and initiating cell death. In this review, we summarize our current understanding of the mechanisms whereby mitochondrial ROS generation occurs in I/R and contributes to myocardial infarction and stroke. In addition, mitochondrial ROS have been shown to participate in preconditioning by several pharmacologic agents that target potassium channels (e.g., ATP-sensitive potassium (mKATP) channels or large conductance, calcium-activated potassium (mBKCa) channels) to activate cell survival programs that render tissues and organs more resistant to the deleterious effects of I/R. Finally, we review novel therapeutic approaches that selectively target mROS production to reduce postischemic tissue injury, which may prove efficacious in limiting myocardial dysfunction and infarction and abrogating neurocognitive deficits and neuronal cell death in stroke.
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Affiliation(s)
- Theodore Kalogeris
- Department of Medical Pharmacology and Physiology, School of Medicine, Dalton Cardiovascular Research Center, University of Missouri, 1 Hospital Drive, Columbia, MO 65212-0001, United States of America
| | - Yimin Bao
- Department of Medical Pharmacology and Physiology, School of Medicine, Dalton Cardiovascular Research Center, University of Missouri, 1 Hospital Drive, Columbia, MO 65212-0001, United States of America
| | - Ronald J Korthuis
- Department of Medical Pharmacology and Physiology, School of Medicine, Dalton Cardiovascular Research Center, University of Missouri, 1 Hospital Drive, Columbia, MO 65212-0001, United States of America
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44
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Hernández-Reséndiz S, Zazueta C. PHO-ERK1/2 interaction with mitochondria regulates the permeability transition pore in cardioprotective signaling. Life Sci 2014; 108:13-21. [PMID: 24835217 DOI: 10.1016/j.lfs.2014.04.037] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2014] [Revised: 04/03/2014] [Accepted: 04/30/2014] [Indexed: 12/24/2022]
Abstract
AIMS The molecular mechanism(s) by which extracellular signal-regulated kinase 1/2 (ERK1/2) and other kinases communicate with downstream targets have not been fully determined. Multiprotein signaling complexes undergoing spatiotemporal redistribution may enhance their interaction with effector proteins promoting cardioprotective response. Particularly, it has been proposed that some active kinases in association with caveolae may converge into mitochondria. Therefore, in this study we investigate if PHO-ERK1/2 interaction with mitochondria may provide a mechanistic link in the regulation of these organelles in cardioprotective signaling. MAIN METHODS Using a model of dilated cardiomyopathy followed by ischemia-reperfusion injury, we determined ERK1/2 signaling at the level of mitochondria and evaluated its effect on the permeability transition pore. KEY FINDINGS The most important finding of the present study is that, under cardioprotective conditions, a subpopulation of activated ERK1/2 was directed to the mitochondrial membranes through vesicular trafficking, concurring with increased phosphorylation of mitochondrial proteins and inhibition of the mitochondrial permeability transition pore opening. In addition, our results suggest that vesicles enriched with caveolin-3 could form structures that may drive ERK1/2, GSK3β and Akt to mitochondria. SIGNIFICANCE Signaling complexes including PHO-ERK, PHO-Akt, PHO-eNOS and caveolin-3 contribute to cardioprotection by directly targeting the mitochondrial proteome and regulating the opening of the permeability transition pore in this model.
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Affiliation(s)
- Sauri Hernández-Reséndiz
- Department of Cardiovascular Biomedicine, National Institute of Cardiology, I.Ch., Juan Badiano No. 1, Colonia Sección XVI, Mexico 14080, DF, Mexico
| | - Cecilia Zazueta
- Department of Cardiovascular Biomedicine, National Institute of Cardiology, I.Ch., Juan Badiano No. 1, Colonia Sección XVI, Mexico 14080, DF, Mexico.
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45
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Pong T, Scherrer-Crosbie M, Atochin DN, Bloch KD, Huang PL. Phosphomimetic modulation of eNOS improves myocardial reperfusion and mimics cardiac postconditioning in mice. PLoS One 2014; 9:e85946. [PMID: 24465805 PMCID: PMC3897570 DOI: 10.1371/journal.pone.0085946] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Accepted: 12/04/2013] [Indexed: 12/16/2022] Open
Abstract
Objective Myocardial infarction resulting from ischemia-reperfusion injury can be reduced by cardiac postconditioning, in which blood flow is restored intermittently prior to full reperfusion. Although key molecular mechanisms and prosurvival pathways involved in postconditioning have been identified, a direct role for eNOS-derived NO in improving regional myocardial perfusion has not been shown. The objective of this study is to measure, with high temporal and spatial resolution, regional myocardial perfusion during ischemia-reperfusion and postconditioning, in order to determine the contribution of regional blood flow effects of NO to infarct size and protection. Methods and Results We used myocardial contrast echocardiography to measure regional myocardial blood flow in mice over time. Reperfusion after myocardial ischemia-reperfusion injury is improved by postconditioning, as well as by phosphomimetic eNOS modulation. Knock-in mice expressing a phosphomimetic S1176D form of eNOS showed improved myocardial reperfusion and significantly reduced infarct size. eNOS knock-out mice failed to show cardioprotection from postconditioning. The size of the no-reflow zone following ischemia-reperfusion is substantially reduced by postconditioning and by the phosphomimetic eNOS mutation. Conclusions and Significance Using myocardial contrast echocardiography, we show that temporal dynamics of regional myocardial perfusion restoration contribute to reduced infarct size after postconditioning. eNOS has direct effects on myocardial blood flow following ischemia-reperfusion, with reduction in the size of the no-reflow zone. These results have important implications for ongoing clinical trials on cardioprotection, because the degree of protective benefit may be significantly influenced by the regional hemodynamic effects of eNOS-derived NO.
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Affiliation(s)
- Terrence Pong
- Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, United States of America
- Harvard-MIT Division of Health Sciences & Technology, Cambridge, Massachusetts, United States of America
| | - Marielle Scherrer-Crosbie
- Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Cardiac Ultrasound Laboratory, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America
| | - Dmitriy N. Atochin
- Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America
| | - Kenneth D. Bloch
- Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America
| | - Paul L. Huang
- Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, United States of America
- Harvard-MIT Division of Health Sciences & Technology, Cambridge, Massachusetts, United States of America
- * E-mail:
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46
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Krenz M, Baines C, Kalogeris T, Korthuis R. Cell Survival Programs and Ischemia/Reperfusion: Hormesis, Preconditioning, and Cardioprotection. ACTA ACUST UNITED AC 2013. [DOI: 10.4199/c00090ed1v01y201309isp044] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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47
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Wang C, Liu N, Luan R, Li Y, Wang D, Zou W, Xing Y, Tao L, Cao F, Wang H. Apelin protects sarcoplasmic reticulum function and cardiac performance in ischaemia-reperfusion by attenuating oxidation of sarcoplasmic reticulum Ca2+-ATPase and ryanodine receptor. Cardiovasc Res 2013; 100:114-24. [DOI: 10.1093/cvr/cvt160] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
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48
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Zhang Y, Xing F, Zheng H, Xi J, Cui X, Xu Z. Roles of mitochondrial Src tyrosine kinase and zinc in nitric oxide-induced cardioprotection against ischemia/reperfusion injury. Free Radic Res 2013; 47:517-25. [DOI: 10.3109/10715762.2013.796044] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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49
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Xu Z, Lee S, Han J. Dual role of cyclic GMP in cardiac cell survival. Int J Biochem Cell Biol 2013; 45:1577-84. [PMID: 23660294 DOI: 10.1016/j.biocel.2013.04.027] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Revised: 04/08/2013] [Accepted: 04/29/2013] [Indexed: 10/26/2022]
Abstract
It is well known that cyclic guanosine 3',5'-monophosphate plays an important role in cardioprotection against ischemia/reperfusion injury through activation of protein kinase G (PKG). We found that cGMP prevents the mitochondrial permeability transition pore (mPTP) opening by inactivating glycogen synthase kinase 3β (GSK-3β) via protein kinase G (PKG) in cardiac H9c2 cells. While GSK-3β and its major upstream regulator phosphoinositide 3-kinase (PI3K)/Akt are critical for acute cardioprotection, an excessive activation of PI3K/Akt or GSK-3β inactivation can also lead to cardiac hypertrophy. Here, we show that cGMP not only inactivates GSK-3β through PKG (this leads to acute cardioprotection) but also negatively regulates Akt activity (this may lead to prevention of hypertrophy and heart failure, and the regulation of NO synthesis) in cardiac cells. We further found that the negative regulatory effect of cGMP on Akt activity is not mediated by PKG but may be through up-regulation of protein phosphatase PP2A activity. We propose that cGMP is a versatile signal with dual beneficial role in cardiac cell survival.
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Affiliation(s)
- Zhelong Xu
- Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China.
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50
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Jacob KD, Hooten NN, Trzeciak AR, Evans MK. Markers of oxidant stress that are clinically relevant in aging and age-related disease. Mech Ageing Dev 2013; 134:139-57. [PMID: 23428415 PMCID: PMC3664937 DOI: 10.1016/j.mad.2013.02.008] [Citation(s) in RCA: 176] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Revised: 02/06/2013] [Accepted: 02/09/2013] [Indexed: 11/20/2022]
Abstract
Despite the long held hypothesis that oxidant stress results in accumulated oxidative damage to cellular macromolecules and subsequently to aging and age-related chronic disease, it has been difficult to consistently define and specifically identify markers of oxidant stress that are consistently and directly linked to age and disease status. Inflammation because it is also linked to oxidant stress, aging, and chronic disease also plays an important role in understanding the clinical implications of oxidant stress and relevant markers. Much attention has focused on identifying specific markers of oxidative stress and inflammation that could be measured in easily accessible tissues and fluids (lymphocytes, plasma, serum). The purpose of this review is to discuss markers of oxidant stress used in the field as biomarkers of aging and age-related diseases, highlighting differences observed by race when data is available. We highlight DNA, RNA, protein, and lipid oxidation as measures of oxidative stress, as well as other well-characterized markers of oxidative damage and inflammation and discuss their strengths and limitations. We present the current state of the literature reporting use of these markers in studies of human cohorts in relation to age and age-related disease and also with a special emphasis on differences observed by race when relevant.
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Affiliation(s)
- Kimberly D. Jacob
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | - Nicole Noren Hooten
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | - Andrzej R. Trzeciak
- Molecular Neurobiology Research Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA
| | - Michele K. Evans
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
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