Deficiency of S100 calcium binding protein A9 attenuates vascular dysfunction in aged mice
Boying Zhao,
Jiang Yu,
Yuan Luo,
Ming Xie,
Can Qu,
Qiong Shi,
Xiaowen Wang,
Xingji Zhao,
Lingwen Kong,
Yu Zhao,
Yongzheng Guo
Affiliations
Boying Zhao
Vascular 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
Jiang Yu
Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
Yuan Luo
Department of Cardiothoracic Surgery, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing University, Chongqing, 400010, China
Ming Xie
Department of Cardiothoracic Surgery, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing University, Chongqing, 400010, China
Can Qu
Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
Qiong Shi
The Department of Laboratory Medicine, M.O.E. Key Laboratory of Laboratory Medical Diagnostics, Chongqing Medical University, Chongqing, 400016, China
Xiaowen Wang
Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
Xingji Zhao
Department of Cardiothoracic Surgery, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing University, Chongqing, 400010, China; Chongqing Key Laboratory of Emergency Medicine, Chongqing, 400010, China
Lingwen Kong
Department of Cardiothoracic Surgery, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing University, Chongqing, 400010, China; Chongqing Key Laboratory of Emergency Medicine, Chongqing, 400010, China
Yu Zhao
Vascular Surgery Department, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China; Corresponding author.
Yongzheng Guo
Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; Corresponding author.
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.
