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Deletion of stimulator of interferons genes aggravated cardiac dysfunction in physiological aged mice
Diansa Gao1, Boying Zhao2, Jiang Yu1
1Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Background:
Stimulator of interferons genes (STING) is crucial for innate immune response. It has been demonstrated that cGAS-STING pathway was the driver of aging-related inflammation. However, whether STING is involved in cardiac dysfunction during the physiological aging process remains unclear.
Methods:
Gene expression profiles were obtained from the Gene Expression Omnibus database, followed by weighted gene co-expression network analysis, gene ontology analysis and protein network interaction analysis to identify key pathway and genes associated with aging. The effects of STING on cardiac function, glucose homeostasis, inflammation, and autophagy in physiological aging were investigated with STING knockout mice.
Results:
Bioinformatics analysis revealed STING emerged as a hub gene of interest. Subsequent experiments demonstrated the activation of STING pathway in the heart of aged mice. Knockout of STING alleviated the inflammation in aged mice. However, Knockout of STING impaired glucose tolerance, inhibited autophagy, enhanced oxidative stress and aggravated cardiac dysfunction in aged mice.
Conclusion:
Although reducing inflammation, long-term STING inhibition by genetic ablation exacerbated cardiac dysfunction in aged mice. Given the multifaceted nature of aging and the diverse cellular functions of STING beyond immune regulation, the negative effects of targeting STING as a strategy to mitigate aging phenotype should be fully considered.
Insights
In aged mice, blocking Stimulator of Interferons Genes (STING) reduced inflammation but worsened heart dysfunction and glucose issues. STING plays a complex role in aging.
Area of Science:
- Immunology
- Cardiology
- Gerontology
Background:
- The stimulator of interferons genes (STING) pathway is vital for innate immunity and implicated in aging-related inflammation.
- Its specific role in cardiac dysfunction during physiological aging is not well understood.
Purpose of the Study:
- To investigate the role of STING in cardiac function during physiological aging.
- To determine the effects of STING modulation on cardiac function, metabolism, and inflammation in aged mice.
Main Methods:
- Bioinformatic analyses (WGCNA, GO, protein-protein interaction) of gene expression data to identify aging-related pathways and genes.
- Utilized STING knockout mice to assess cardiac function, glucose homeostasis, inflammation, and autophagy in aged conditions.
Main Results:
- STING was identified as a key hub gene associated with aging, with its pathway activated in aged mouse hearts.
- STING knockout alleviated inflammation but impaired glucose tolerance, inhibited autophagy, increased oxidative stress, and aggravated cardiac dysfunction in aged mice.
Conclusions:
- While STING inhibition reduces inflammation, long-term genetic ablation exacerbates cardiac dysfunction in aging.
- Targeting STING to mitigate aging phenotypes requires careful consideration due to its multifaceted roles beyond immune regulation.
