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

doi:10.3389/fimmu.2022.870811

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

Front Immunol. 2022 Apr 1:13:870811. doi: 10.3389/fimmu.2022.870811. eCollection 2022.

Authors

M-K Torp¹, T Ranheim^{2

3}, C Schjalm⁴, M Hjorth⁵, C M Heiestad¹, K T Dalen⁵, P H Nilsson^{4

6}, T E Mollnes^{4

7

8

9}, S E Pischke^{4

10}, E Lien^{9

11}, J Vaage^{1

10

12}, A Yndestad², K-O Stensløkken¹

Affiliations

¹ Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
² Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway.
³ Division of Surgery, Inflammatory Diseases and Transplantation, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁴ Department of Immunology, Institute of Clinical Medicine University of Oslo, Oslo, Norway.
⁵ Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
⁶ Linnaeus Centre for Biomaterials Chemistry, and the Department of Chemistry and Biomedicine, Linnaeus University, Kalmar, Sweden.
⁷ Stiftelsen Kristian Gerhard Jebsen (K.G. Jebsen) Inflammation Research Center (IRC), University of Oslo, Oslo, Norway.
⁸ 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.
⁹ Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
¹⁰ Department of Research & Development, Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway.
¹¹ Division of Infectious Diseases and Immunology, Program in Innate Immunity, Department of Medicine, UMass Medical School, Worchester, MA, United States.
¹² Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

Abstract

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.

Keywords: cardiology (basic/technical); complement system; intracellular C3; ischemia-reperfusion injury; metabolism.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Complement C3
Homeostasis
Male
Mice
Myocardial Infarction* / metabolism
Myocardial Reperfusion Injury* / metabolism
Myocytes, Cardiac / metabolism

Substances

Complement C3