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Published on: May 31, 2016
Deficiency of S100 calcium binding protein A9 attenuates vascular dysfunction in aged mice
Boying Zhao1, Jiang Yu2, Yuan Luo3
1Vascular Surgery Department, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China; Department of Cardiothoracic Surgery, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing University, Chongqing, 400010, China.
Insights
S100 calcium-binding protein A9 (S100A9) drives vascular aging and inflammation. Removing S100A9 improved vascular function and reduced aging markers in mice, suggesting a therapeutic target for cardiovascular disease.
Area of Science:
- Molecular Biology
- Cardiovascular Research
- Aging Biology
Background:
- S100 calcium-binding protein A9 (S100A9) is a key mediator of inflammation, a critical factor in age-related cardiovascular diseases.
- The specific role of S100A9 in the process of vascular aging remains largely unexplored.
- Understanding S100A9's function in vascular aging is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of S100A9 in aging-related vascular pathologies.
- To elucidate the molecular mechanisms by which S100A9 influences vascular senescence and endothelial dysfunction.
- To assess the therapeutic potential of targeting the S100A9 pathway in age-related cardiovascular conditions.
Main Methods:
- Utilized S100A9 null mice to assess the impact of S100A9 deficiency on aging pathologies.
- Employed pressurized myography to evaluate vascular ring function and measured senescence markers including telomere length, Sirtuin activity, oxidative stress, and eNOS activity.
- Assessed insulin resistance via IPGTT and IST, and analyzed inflammatory cytokine concentrations. Investigated downstream mechanisms using TLR4 and RAGE inhibitors in endothelial cells.
Main Results:
- S100A9 expression increased with age in vasculature of mice and humans.
- S100A9 deficiency ameliorated vascular senescence, improved endothelium-dependent vasodilation, and enhanced endothelial continuity in aged mice.
- S100A9 knockout mitigated insulin resistance, oxidative stress, and inflammation. In vitro, S100A9-induced endothelial cell senescence was dependent on TLR4 signaling.
Conclusions:
- S100A9 significantly contributes to vascular aging and endothelial dysfunction, primarily through the Toll-like receptor 4 (TLR4) pathway.
- Targeting the S100A9/TLR4 signaling pathway presents a promising therapeutic strategy for preventing age-related cardiovascular diseases.
- These findings highlight S100A9 as a potential therapeutic target for mitigating vascular aging and its associated cardiovascular complications.
Background:
S100 calcium-binding protein A9 (S100A9) is a danger-associated molecular pattern molecule that mediates the inflammatory response. Inflammation is essential in aging-related cardiovascular diseases. However, less is known regarding the role of S100A9 in vascular aging.
Methods:
S100A9 null mice were used to investigate the role of S100A9 in aging-related pathologies. Artery rings were used to measure the functional characteristics of vascular with a pressurized myograph. Telomere length, Sirtuin activity, oxidative stress, and endothelial nitric oxide synthetase (eNOS) activity were used to elevate vascular senescence. Intraperitoneal glucose tolerance (IPGTT) and insulin sensitivity test (IST) were employed to investigate the effects of S100A9 on insulin resistance. Inflammation response was reflected by the concentration of inflammatory cytokines. The Toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE) inhibitors were used to identify the downstream molecular mechanisms of S100A9 in aging-induced senescence in endothelial cells.
Results:
S100A9 expression in vascular increased with aging in mice and humans. Deficiency of S100A9 alleviated vascular senescence in aged mice, as evidenced by increased telomere length, Sirtuin activity, and eNOS activity. Meanwhile, S100A9 knockout improved endothelium-dependent vasodilatation and endothelial continuity in aged mice. Moreover, the increased insulin resistance, oxidative stress, and inflammation were mitigated by S100A9 deletion in aged mice. In vitro, S100A9 induced senescence in endothelial cells, and that effect was blunted by TLR4 but not RAGE inhibitors.
Conclusion:
The present study suggested that S100A9 may contribute to aging-related pathologies and endothelial dysfunction via the TLR4 pathway. Therefore, targeting S100A9/TLR4 signaling pathway may represent a crucial therapeutic strategy to prevent age-related cardiovascular diseases.
