Oscillatory shear stress promotes endothelial senescence and atherosclerosis via STING activation

• Published in: Biochemical and biophysical research communications Vol. 715; p. 149979
• Main Authors: Dong, Mengdie, Chen, Minghong, Zhang, Yunjia, He, Xian, Min, Jiao, Tan, Yongkang, Wei, Huiyuan, Li, Xinyu, Chen, Xiang, Zheng, Longbin, Yin, Quanwen, Li, Xuesong, Chen, Hongshan, Jiang, Hong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.06.2024
• Subjects: Animals; atherogenesis; Atherosclerosis; Atherosclerosis - genetics; Atherosclerosis - metabolism; Atherosclerosis - pathology; blood flow; Cells, Cultured; Cellular Senescence - genetics; Diet, High-Fat; DNA, Mitochondrial - genetics; DNA, Mitochondrial - metabolism; Endothelial Cells - metabolism; Endothelial Cells - pathology; Endothelial senescence; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; high fat diet; Humans; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; mitochondria; Mitochondria - metabolism; Mitochondria - pathology; mitochondrial DNA; Oscillatory shear stress; shear stress; STING; Stress, Mechanical; therapeutics; STING; Oscillatory shear stress; Atherosclerosis; Endothelial senescence
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2024.149979

Endothelial dysfunction is an initiating factor in atherosclerosis. Endothelial cells (ECs) are constantly subject to blood flow shear stress, and atherosclerotic plaques tend to occur in aortic bends or bifurcations impaired by low oscillatory shear stress (OSS). However, the mechanism that how OSS affects the initiation and progression of atherosclerosis remains to be explored. Here, we first reported that OSS can promote endothelial dysfunction and atherogenesis in vivo and in vitro by activating STING pathway. Mechanistically, at atherosclerosis-prone areas, OSS caused mitochondria damage in ECs, leading to the leakage of mitochondrial DNA (mtDNA) into the cytoplasm. The cytoplasmic mtDNA was recognized by cGAS to produce cGAMP, activating the STING pathway and leading to endothelial senescence, which resulted in endothelial dysfunction and atherosclerosis. We found that STING was activated in plaques of atherosclerotic patients and in aortic arch ECs of high-fat diet (HFD)-fed ApoeKO mice, as well as in ECs exposed to OSS. STING-specific deficiency in ECs attenuates endothelial senescence and resulted in a significant reduction in aortic arch plaque area in HFD-fed ApoeKO mice. Consistently, specific deficiency or pharmacological inhibition of STING attenuated OSS-induced senescence and endothelial dysfunction. Pharmacological depletion of mtDNA ameliorated OSS-induced senescence and endothelial dysfunction. Taken together, our study linked hemodynamics and endothelial senescence, and revealed a novel mechanism by which OSS leads to endothelial dysfunction. Our study provided new insights into the development of therapeutic strategies for endothelial senescence and atherosclerosis. Schematic diagram showed that in vascular regions with disturbed aortic flow, oscillatory shear stress induces mitochondrial DNA leakage is responsible for endothelial cell senescence via mediating STING signaling pathway activation, which in turn promotes endothelial dysfunction and atherosclerosis by increasing endothelial cell barrier permeability. [Display omitted] •Oscillatory shear stress promotes atherosclerosis via inducing STING activation.•Activation of STING pathway induces endothelial cell senescence in atherosclerosis.•Oscillatory shear stress mediating STING activation via mitochondrial DNA leakage.