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      Activation of complement factor B contributes to murine and human myocardial ischemia/reperfusion injury

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          Abstract

          The pathophysiology of myocardial injury that results from cardiac ischemia and reperfusion (I/R) is incompletely understood. Experimental evidence from murine models indicates that innate immune mechanisms including complement activation via the classical and lectin pathways are crucial. Whether factor B (fB), a component of the alternative complement pathway required for amplification of complement cascade activation, participates in the pathophysiology of myocardial I/R injury has not been addressed. We induced regional myocardial I/R injury by transient coronary ligation in WT C57BL/6 mice, a manipulation that resulted in marked myocardial necrosis associated with activation of fB protein and myocardial deposition of C3 activation products. In contrast, in fB -/- mice, the same procedure resulted in significantly reduced myocardial necrosis (% ventricular tissue necrotic; fB -/- mice, 20 ± 4%; WT mice, 45 ± 3%; P < 0.05) and diminished deposition of C3 activation products in the myocardial tissue (fB -/- mice, 0 ± 0%; WT mice, 31 ± 6%; P<0.05). Reconstitution of fB -/- mice with WT serum followed by cardiac I/R restored the myocardial necrosis and activated C3 deposition in the myocardium. In translational human studies we measured levels of activated fB (Bb) in intracoronary blood samples obtained during cardio-pulmonary bypass surgery before and after aortic cross clamping (AXCL), during which global heart ischemia was induced. Intracoronary Bb increased immediately after AXCL, and the levels were directly correlated with peripheral blood levels of cardiac troponin I, an established biomarker of myocardial necrosis (Spearman coefficient = 0.465, P < 0.01). Taken together, our results support the conclusion that circulating fB is a crucial pathophysiological amplifier of I/R-induced, complement-dependent myocardial necrosis and identify fB as a potential therapeutic target for prevention of human myocardial I/R injury.

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          Regulation of signal transduction by reactive oxygen species in the cardiovascular system.

          Oxidative stress has long been implicated in cardiovascular disease, but more recently, the role of reactive oxygen species (ROS) in normal physiological signaling has been elucidated. Signaling pathways modulated by ROS are complex and compartmentalized, and we are only beginning to identify the molecular modifications of specific targets. Here, we review the current literature on ROS signaling in the cardiovascular system, focusing on the role of ROS in normal physiology and how dysregulation of signaling circuits contributes to cardiovascular diseases, including atherosclerosis, ischemia-reperfusion injury, cardiomyopathy, and heart failure. In particular, we consider how ROS modulate signaling pathways related to phenotypic modulation, migration and adhesion, contractility, proliferation and hypertrophy, angiogenesis, endoplasmic reticulum stress, apoptosis, and senescence. Understanding the specific targets of ROS may guide the development of the next generation of ROS-modifying therapies to reduce morbidity and mortality associated with oxidative stress.
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            Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies.

            Clinical and experimental data indicate that anti-neutrophil cytoplasmic autoantibodies (ANCAs) cause glomerulonephritis and vasculitis. Here we report the first evidence that complement is an important mediator of ANCA disease. Transfer of anti-myeloperoxidase (MPO) IgG into wild-type mice or anti-MPO splenocytes into immune-deficient mice caused crescentic glomerulonephritis that could be completely blocked by complement depletion. The role of specific complement activation pathways was investigated using mice with knockout of the common pathway component C5, classic and lectin binding pathway component C4, and alternative pathway component factor B. After injection of anti-MPO IgG, C4-/- mice developed disease comparable with wild-type disease; however, C5-/- and factor B-/- mice developed no disease. To substantiate a role for complement in human ANCA disease, IgG was isolated from patients with myeloperoxidase ANCA (MPO-ANCA) or proteinase 3 ANCA (PR3-ANCA) and from controls. Incubation of MPO-ANCA or PR3-ANCA IgG with human neutrophils caused release of factors that activated complement. IgG from healthy controls did not produce this effect. The findings suggest that stimulation of neutrophils by ANCA causes release of factors that activate complement via the alternative pathway, thus initiating an inflammatory amplification loop that mediates the severe necrotizing inflammation of ANCA disease.
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              The mitochondrial permeability transition: a current perspective on its identity and role in ischaemia/reperfusion injury.

              The mitochondrial permeability transition pore (MPTP) is a non-specific pore that opens in the inner mitochondrial membrane (IMM) when matrix [Ca(2+)] is high, especially when accompanied by oxidative stress, high [Pi] and adenine nucleotide depletion. Such conditions occur during ischaemia and subsequent reperfusion, when MPTP opening is known to occur and cause irreversible damage to the heart. Matrix cyclophilin D facilitates MPTP opening and is the target of its inhibition by cyclosporin A that is cardioprotective. Less certainty exists over the composition of the pore itself, with structural and/or regulatory roles proposed for the adenine nucleotide translocase, the phosphate carrier and the FoF1 ATP synthase. Here we critically review the supporting data for the role of each and suggest that they may interact with each other through their bound cardiolipin to form the ATP synthasome. We propose that under conditions favouring MPTP opening, calcium-triggered conformational changes in these proteins may perturb the interface between them generating the pore. Proteins associated with the outer mitochondrial membrane (OMM), such as members of the Bcl-2 family and hexokinase (HK), whilst not directly involved in pore formation, may regulate MPTP opening through interactions between OMM and IMM proteins at "contact sites". Recent evidence suggests that cardioprotective protocols such as preconditioning inhibit MPTP opening at reperfusion by preventing the loss of mitochondrial bound HK2 that stabilises these contact sites. Contact site breakage both sensitises the MPTP to [Ca(2+)] and facilitates cytochrome c loss from the intermembrane space leading to greater ROS production and further MPTP opening. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease".
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: Visualization
                Role: Data curationRole: Formal analysisRole: InvestigationRole: Visualization
                Role: Data curationRole: Formal analysisRole: InvestigationRole: Visualization
                Role: Data curationRole: InvestigationRole: MethodologyRole: Resources
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: Investigation
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Validation
                Role: Data curationRole: Investigation
                Role: Data curationRole: Investigation
                Role: Data curationRole: InvestigationRole: MethodologyRole: Resources
                Role: Data curationRole: InvestigationRole: Resources
                Role: MethodologyRole: Resources
                Role: Data curationRole: Investigation
                Role: Data curationRole: Investigation
                Role: Data curationRole: Formal analysisRole: InvestigationRole: Visualization
                Role: Data curationRole: Formal analysisRole: Investigation
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Resources
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                29 June 2017
                2017
                : 12
                : 6
                : e0179450
                Affiliations
                [1 ]Nephrology Division, Department of Medicine and Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
                [2 ]Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut, United States of America
                [3 ]Department of Anesthesiology, College of Medicine, SUNY Downstate Medical Center, Brooklyn, New York, United States of America
                [4 ]Department of Surgery, College of Medicine, SUNY Downstate Medical Center, Brooklyn, New York, United States of America
                [5 ]Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, United States of America
                [6 ]Department of Medical Chemistry and Cell Biology, Göteborg University, Göteborg, Sweden
                [7 ]Department of Biomedical Sciences, Long Island University, Brookville, New York, United States of America
                [8 ]Department of Cell Biology, College of Medicine, SUNY Downstate Medical Center, Brooklyn, New York, United States of America
                Macau University of Science and Technology, MACAO
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-5836-0960
                Article
                PONE-D-16-51556
                10.1371/journal.pone.0179450
                5491012
                28662037
                548d1b6f-5e95-40ec-99fa-3929b9022b78
                © 2017 Chun et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 3 January 2017
                : 29 May 2017
                Page count
                Figures: 5, Tables: 2, Pages: 23
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: 1R21HL088527
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: 1R21AI117695-01
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100004856, New York State Department of Health;
                Award ID: ECRIP Award
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: 5T32DK007757
                Award Recipient :
                The research was funded in part by NIH grant 1R21HL088527(MZ) and 1R21AI117695-01 (PSH and MZ) and an ECRIP Award from New York State Department of Health (KS and MZ). Dr. Yunfang Hou is an ECRIP fellow. NC is supported by T32 (5T32DK007757).
                Categories
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                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Necrosis
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                Necrosis
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                Custom metadata
                Unrestricted data are included in the paper and its Supporting Information files. Some data are restricted to protect participant confidentiality, and are available from the SUNY Downstate Medical Center and Yale University School of Medicine Institutional Data Access / Ethics Committee for researchers who meet the criteria for access to confidential data. Researchers may contact Dr. Ming Zhang at ming.zhang@ 123456downstate.edu to request data access. Additional non-author contact: Kevin L. Nellis, MS, CIP, Executive Director, Human Research Protection & Quality Assurance, SUNY Downstate Medical Center, Tel: (718) 613-8461; email: Kevin.Nellis@ 123456downstate.edu .

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