Intracellular Complement Component 3 Attenuated Ischemia-Reperfusion Injury in the Isolated Buffer-Perfused Mouse Heart and Is Associated With Improved Metabolic Homeostasis

M-K. Torp; T. Ranheim; T. Ranheim; C. Schjalm; M. Hjorth; C.M. Heiestad; K. T. Dalen; P. H. Nilsson; P. H. Nilsson; T. E. Mollnes; T. E. Mollnes; T. E. Mollnes; T. E. Mollnes; S. E. Pischke; S. E. Pischke; E. Lien; E. Lien; J. Vaage; J. Vaage; J. Vaage; A. Yndestad; K-O. Stensløkken

doi:10.3389/fimmu.2022.870811

Frontiers in Immunology (Apr 2022)

Intracellular Complement Component 3 Attenuated Ischemia-Reperfusion Injury in the Isolated Buffer-Perfused Mouse Heart and Is Associated With Improved Metabolic Homeostasis

M-K. Torp,
T. Ranheim,
T. Ranheim,
C. Schjalm,
M. Hjorth,
C.M. Heiestad,
K. T. Dalen,
P. H. Nilsson,
P. H. Nilsson,
T. E. Mollnes,
T. E. Mollnes,
T. E. Mollnes,
T. E. Mollnes,
S. E. Pischke,
S. E. Pischke,
E. Lien,
E. Lien,
J. Vaage,
J. Vaage,
J. Vaage,
A. Yndestad,
K-O. Stensløkken

Affiliations

M-K. Torp: Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
T. Ranheim: Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
T. Ranheim: Division of Surgery, Inflammatory Diseases and Transplantation, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
C. Schjalm: Department of Immunology, Institute of Clinical Medicine University of Oslo, Oslo, Norway
M. Hjorth: Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
C.M. Heiestad: Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
K. T. Dalen: Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
P. H. Nilsson: Department of Immunology, Institute of Clinical Medicine University of Oslo, Oslo, Norway
P. H. Nilsson: Linnaeus Centre for Biomaterials Chemistry, and the Department of Chemistry and Biomedicine, Linnaeus University, Kalmar, Sweden
T. E. Mollnes: Department of Immunology, Institute of Clinical Medicine University of Oslo, Oslo, Norway
T. E. Mollnes: Stiftelsen Kristian Gerhard Jebsen (K.G. Jebsen) Inflammation Research Center (IRC), University of Oslo, Oslo, Norway
T. E. Mollnes: Research Laboratory, Nordland Hospital, Bodø, and Faculty of Health Sciences, Stiftelsen Kristian Gerhard Jebsen (K.G. Jebsen) Thrombosis Research and Expertise Center (TREC), University of Tromsø, Tromsø, Norway
T. E. Mollnes: Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
S. E. Pischke: Department of Immunology, Institute of Clinical Medicine University of Oslo, Oslo, Norway
S. E. Pischke: 0Department of Research & Development, Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway
E. Lien: Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
E. Lien: 1Division of Infectious Diseases and Immunology, Program in Innate Immunity, Department of Medicine, UMass Medical School, Worchester, MA, United States
J. Vaage: Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
J. Vaage: 0Department of Research & Development, Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway
J. Vaage: 2Institute of Clinical Medicine, University of Oslo, Oslo, Norway
A. Yndestad: Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
K-O. Stensløkken: Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway

DOI: https://doi.org/10.3389/fimmu.2022.870811
Journal volume & issue: Vol. 13

Abstract

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The innate immune system is rapidly activated during myocardial infarction and blockade of extracellular complement system reduces infarct size. Intracellular complement, however, appears to be closely linked to metabolic pathways and its role in ischemia-reperfusion injury is unknown and may be different from complement activation in the circulation. The purpose of the present study was to investigate the role of intracellular complement in isolated, retrogradely buffer-perfused hearts and cardiac cells from adult male wild type mice (WT) and from adult male mice with knockout of complement component 3 (C3KO). Main findings: (i) Intracellular C3 protein was expressed in isolated cardiomyocytes and in whole hearts, (ii) after ischemia-reperfusion injury, C3KO hearts had larger infarct size (32 ± 9% in C3KO vs. 22 ± 7% in WT; p=0.008) and impaired post-ischemic relaxation compared to WT hearts, (iii) C3KO cardiomyocytes had lower basal oxidative respiration compared to WT cardiomyocytes, (iv) blocking mTOR decreased Akt phosphorylation in WT, but not in C3KO cardiomyocytes, (v) after ischemia, WT hearts had higher levels of ATP, but lower levels of both reduced and oxidized nicotinamide adenine dinucleotide (NADH and NAD+, respectively) compared to C3KO hearts. Conclusion: intracellular C3 protected the heart against ischemia-reperfusion injury, possibly due to its role in metabolic pathways important for energy production and cell survival.

Published in Frontiers in Immunology

ISSN: 1664-3224 (Online)
Publisher: Frontiers Media S.A.
Country of publisher: Switzerland
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Immunologic diseases. Allergy
Website: http://journal.frontiersin.org/journal/immunology

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