Abstract

Although accumulation of senescent vascular endothelial cells impairs the vessel homeostasis and promote atherosclerotic diseases, underlying mechanisms are largely unknown. We found that Senescence associated glycoprotein (SAGP) expression was significantly increased in human endothelial cells undergoing replicative senescence. SAGP expression in aorta was significantly increased in Apo-E knockout mice. Furthermore, mean SAGP expression was significantly higher in the leukocytes of the patients with atherosclerotic diseases.These data suggest that SAGP would become the novel cellular senescence and/or atherosclerotic disease marker. The genetic deletion of SAGP resulted in high level of mitochondrial reactive oxygen species (ROS) and promoted premature senescence in human endothelial cells. And this associated with suppression of mitochondrial autophagy, mitophagy, suggesting that SAGP protect cells from ROS by inducing mitophagy. Thus, wegenerated ApoE-KO / SAGP gain-of-function transgenic mice and found that atherosclerotic plaque burden was attenuated in these transgenic mice. In contrast, in SAGP / ApoE double knockout mice atherosclerosis were impaired. These data suggest that modulation of SAGPwould become a new therapeutic target for atherosclerotic diseases.Recently, it is reported that elimination of senescent cells (senolysis) reversibly improved pathological aging phenotypes. We generated SAGP-DTR (diphtheria toxin receptor) transgenic mice,inducible elimination of SAGP positive senescent cells upon administration of diphtheria toxin. Elimination of SAGP expressing cells significantly reduced the atherosclerotic plaque burden. Furthermore, we developed a cytotoxic vaccine targeting SAGP. Administration of SAGP vaccine to ApoE-KO mice significantly reduced atherogenesis. These data indicate that targeting SAGP-positive cells could be a strategy for senolytic therapy.

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