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Alpha-ketoglutarate protects against myocardial infarction via FTO-mediated anti-inflammatory macrophage activation
Zhijun Lin1,2,3,4, Huan He1,2,3, Pinliang Chen1,2,3
1State Key Laboratory of Traditional Chinese Medicine Syndrome, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
Insights
Alpha-ketoglutarate (AKG) supplementation improves heart function after myocardial infarction by reducing inflammation. This occurs through a novel pathway involving FTO, epigenetic modification of Stat3, and macrophage reprogramming.
Area of Science:
- Cardiovascular Research
- Immunology
- Epigenetics
Background:
- Ischemic heart disease treatment is limited, particularly for post-infarction inflammation and cardiac remodeling.
- The role of tricarboxylic acid (TCA) cycle metabolites in regulating macrophage-driven cardiac inflammation is not well understood.
Purpose of the Study:
- To investigate if alpha-ketoglutarate (AKG) supplementation can mitigate cardiac dysfunction post-myocardial infarction.
- To explore the mechanisms involving macrophage activation, TCA cycle replenishment, and FTO-dependent epigenetic regulation.
Main Methods:
- Myocardial infarction induced in mice; AKG supplementation administered.
- Assessed cardiac function via echocardiography and infarct size via histopathology.
- Quantified macrophage infiltration (Ly6C+), analyzed FTO's role, and investigated JAK1/STAT3 signaling and Stat3 mRNA m6A methylation (m6A-RIP-qPCR).
Main Results:
- AKG supplementation restored TCA cycle flux and significantly reduced infarct size and pro-inflammatory macrophage infiltration.
- AKG's benefits were dependent on macrophage FTO expression.
- AKG promoted STAT3 nuclear translocation via FTO-mediated Stat3 mRNA demethylation, activating JAK1/STAT3 signaling for anti-inflammatory polarization and metabolic reprogramming.
Conclusions:
- AKG supplementation attenuates post-infarction cardiac dysfunction by regulating macrophage activation through a novel AKG-FTO-m6A-STAT3 pathway.
- This pathway involves FTO-mediated epigenetic modification of Stat3, leading to anti-inflammatory polarization and metabolic reprogramming.
- TCA cycle replenishment emerges as a potential therapeutic strategy for ischemic heart injury.
Abstract:
Ischemic heart disease lacks optimal therapies targeting post-infarction inflammation and remodeling. The role of TCA cycle metabolites in modulating macrophage-driven cardiac inflammation remains unclear. This study hypothesized that AKG supplementation attenuates cardiac dysfunction by regulating macrophage activation via TCA cycle replenishment and FTO-dependent epigenetic mechanisms. Myocardial infarction was induced in male C57BL/6 mice and macrophage-specific FTO knockout mice via left anterior descending artery ligation. Mice received AKG supplementation. Techniques included echocardiography, histopathology, flow cytometry (quantifying Ly6C+ macrophages), m6A-RIP-qPCR (assessing Stat3 mRNA methylation), Western blotting (JAK1/STAT3 pathway), Seahorse metabolic analysis (BMDMs), and in vitro BMDM cultures. Data are mean ± SD; statistical significance (p < 0.05) assessed by t-test/ANOVA. AKG restored TCA cycle flux and significantly reduced infarct size (p < 0.01). It attenuated pro-inflammatory Ly6C+ macrophage infiltration (p < 0.05) versus controls. AKG required macrophage FTO expression, increasing STAT3 nuclear translocation (p < 0.05) via FTO-mediated m6A demethylation of Stat3 mRNA (p < 0.01). This activated JAK1/STAT3 signaling, driving anti-inflammatory polarization and metabolic reprogramming (p < 0.05). AKG supplementation attenuates post-infarction cardiac dysfunction primarily through FTO-mediated m6A demethylation of Stat3 in macrophages, activating JAK1/STAT3 signaling to promote anti-inflammatory polarization and metabolic reprogramming. This defines a novel metabolite-epigenetic pathway (AKG-FTO-m6A-STAT3) for immunomodulation in ischemic injury, highlighting TCA cycle replenishment as a therapeutic strategy.
