Background:Abnormal accumulation of senescent cells in the vessel wall leads to a compromised vascular function contributing to vascular aging. Soluble DPP4 (dipeptidyl peptidase 4; sDPP4) secretion from visceral adipose tissue is enhanced in obesity, now considered a progeric condition. sDPP4 triggers vascular deleterious effects, albeit its contribution to vascular aging is unknown. We aimed to explore sDPP4 involvement in vascular aging, unraveling the molecular pathway by which sDPP4 acts on the endothelium.Methods:Human endothelial cell senescence was assessed by senescence-associated β-galactosidase assay, visualization of DNA damage, and expression of prosenescent markers, whereas vascular function was evaluated by myography over human dissected microvessels. In visceral adipose tissue biopsies from a cohort of obese patients, we explored several age-related parameters in vitro and ex vivo.Results:By a common mechanism, sDPP4 triggers endothelial cell senescence and endothelial dysfunction in isolated human resistance arteries. sDPP4 activates the metabotropic receptor PAR2 (protease-activated receptor 2), COX-2 (cyclooxygenase 2) activity, and the production of TXA₂ (thromboxane A₂) acting over TP (thromboxane receptor) receptors (PAR2–COX-2–TP axis), leading to NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3) inflammasome activation. Obese patients exhibited impaired microarterial functionality in comparison to control nonobese counterparts. Importantly, endothelial dysfunction in obese patients positively correlated with greater expression of DPP4, prosenescent, and proinflammatory markers in visceral adipose tissue nearby the resistance arteries. Moreover, when DPP4 activity or sDPP4-induced prosenescent mechanism was blocked, endothelial dysfunction was restored back to levels of healthy subjects.Conclusions:These results reveal sDPP4 as a relevant mediator in early vascular aging and highlight its capacity activating main proinflammatory mediators in the endothelium that might be pharmacologically tackled.

中文翻译：

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DPP4 通过 PAR2–COX-2–TP 轴和 NLRP3 炎症小体激活促进人类内皮细胞衰老和功能障碍

背景：衰老细胞在血管壁的异常聚集导致血管功能受损，从而导致血管老化。内脏脂肪组织的可溶性 DPP4（二肽基肽酶 4；sDPP4）分泌在肥胖症中增强，现在被认为是一种早衰症。sDPP4 触发血管有害作用，尽管它对血管老化的贡献是未知的。我们旨在探索 sDPP4 参与血管衰老，揭示 sDPP4 作用于内皮的分子途径。而血管功能是通过人体解剖微血管的肌电图来评估的。在一组肥胖患者的内脏脂肪组织活检中，我们在体外和离体探索了几个与年龄相关的参数。结果：通过一个共同的机制，sDPP4 在孤立的人体阻力动脉中触发内皮细胞衰老和内皮功能障碍。sDPP4 激活代谢型受体 PAR2（蛋白酶激活受体 2）、COX-2（环氧合酶 2）活性和 TXA 的产生₂（血栓素 A ₂）作用于 TP（血栓素受体）受体（PAR2-COX-2-TP 轴），导致 NLRP3（核苷酸结合寡聚化结构域、富含亮氨酸的重复序列和含有 pyrin 结构域的 3）炎症小体激活。与对照组非肥胖患者相比，肥胖患者的微动脉功能受损。重要的是，肥胖患者的内皮功能障碍与阻力动脉附近的内脏脂肪组织中 DPP4、衰老和促炎标志物的更多表达呈正相关。此外，当 DPP4 活性或 sDPP4 诱导的衰老机制被阻断时，内皮功能障碍恢复到健康受试者的水平。结论：