Macrophage-derived S100A9 promotes diabetic cardiomyopathy by disturbing mitochondrial quality control via STAT3
Shengqi Huo1,2, Moran Wang1, Min Du1
1Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, China, 430030.
Insights
Macrophage-derived S100A9 drives diabetic cardiomyopathy by impairing mitochondrial function. Blocking S100A9 or its pathway alleviates cardiac dysfunction, offering a potential therapeutic target for diabetic heart disease.
Area of Science:
- Cardiovascular Biology
- Immunology
- Metabolic Disease Research
Background:
- Diabetic cardiomyopathy (DCM) involves complex macrophage-cardiomyocyte interactions.
- The specific role of inflammatory mediators like S100A9 in DCM requires further investigation.
Purpose of the Study:
- To investigate the role of S100A9 in diabetic cardiomyopathy.
- To explore S100A9 as a potential therapeutic target for DCM.
Main Methods:
- Single-cell RNA sequencing to identify S100A9 in diabetic hearts.
- In vivo studies using S100A9 inhibition (paquinimod), macrophage depletion (clodronate), and macrophage-specific S100A9 knockout mice.
- Analysis of cardiac function, inflammation, mitochondrial dynamics, and STAT3 signaling.
Main Results:
- S100A9 was upregulated in cardiomyocytes and macrophages in diabetic hearts.
- Increased F4/80+CCR2+S100A9+ macrophages were observed in diabetic mice.
- S100A9 blockade or depletion ameliorated cardiac dysfunction and inflammation.
- Macrophage-specific S100A9 knockout suppressed DCM, mitochondrial dysfunction, and STAT3 activation.
Conclusions:
- Macrophage-derived S100A9 is a key mediator of mitochondrial dysfunction in DCM.
- Targeting S100A9 presents a promising therapeutic strategy for diabetic cardiomyopathy.
Abstract:
The macrophage-cardiomyocyte crosstalk as a potential intervention target for diabetic cardiomyopathy (DCM) remains deeper exploration. We found S100A9, as an immunoinflammatory mediator, was up-regulated in cardiomyocytes and macrophages in diabetic heart by single-cell analysis. Furthermore, F4/80+CCR2+S100A9+ macrophages in peripheral blood and heart both increased in diabetic mice. S100A9 blocking by paquinimod or macrophage depletion (clodronate) alleviated diabetes-induced cardiac dysfunction, inflammatory macrophage infiltration, serum pro-inflammatory cytokines. More importantly, diabetic cardiac dysfunction, myocardial remodeling, and inflammation could be suppressed by macrophage specific S100A9 knockout (S100a9flox/floxLyz2-Cre). S100A9 activation led to excessive mitochondrial fission, decreased mitophagy flux, and elevated mitochondrial oxidative stress. In addition, proteomics and transcription factor profiling array unveiled S100A9 activated STAT3 in cardiomyocytes. Nevertheless, these effects were mitigated by STAT3(Y705F) mutation, STAT3 knockdown, or paquinimod. Our study highlights macrophage-derived S100A9 as a critical mediator for impaired mitochondrial quality control in diabetic cardiac dysfunction, and targeting S100A9 represents a promising therapeutic target.
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