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Updated: Sep 26, 2025
A Murine Closed-chest Model of Myocardial Ischemia and Reperfusion
Published on: July 17, 2012
Intracellular Complement Component 3 Attenuated Ischemia-Reperfusion Injury in the Isolated Buffer-Perfused Mouse
M-K Torp1, T Ranheim2,3, C Schjalm4
1Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
Insights
Intracellular complement component 3 (C3) protects the heart from damage after ischemia-reperfusion injury. C3 knockout mice showed larger infarct sizes and impaired heart function, highlighting C3's protective role.
Area of Science:
- Cardiovascular Biology
- Immunology
- Cellular Metabolism
Background:
- The innate immune system, including the complement system, is activated during myocardial infarction.
- Extracellular complement blockade reduces infarct size, but the role of intracellular complement in ischemia-reperfusion injury remains unclear.
- Intracellular complement may influence metabolic pathways distinct from circulating complement.
Purpose of the Study:
- To investigate the role of intracellular complement component 3 (C3) in myocardial ischemia-reperfusion injury.
- To compare outcomes in wild-type (WT) mice and C3 knockout (C3KO) mice using isolated heart and cardiac cell models.
Main Methods:
- Utilized isolated, retrogradely buffer-perfused hearts and cardiac cells from adult male WT and C3KO mice.
- Assessed infarct size, post-ischemic relaxation, basal oxidative respiration, and levels of ATP and nicotinamide adenine dinucleotide (NADH/NAD+).
- Investigated the effect of mTOR inhibition on Akt phosphorylation.
Main Results:
- Intracellular C3 protein expression was confirmed in cardiomyocytes and whole hearts.
- C3KO hearts exhibited significantly larger infarct sizes and impaired relaxation post-ischemia compared to WT hearts.
- C3KO cardiomyocytes displayed reduced basal oxidative respiration, and C3 modulated metabolic pathways including ATP and NAD+ levels.
Conclusions:
- Intracellular C3 plays a protective role in the heart against ischemia-reperfusion injury.
- C3's protective effect may be mediated through its involvement in critical metabolic pathways for energy production and cell survival.
- Findings suggest intracellular complement is a potential therapeutic target for cardiac injury.
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.
