肺动脉平滑肌细胞衰老：低氧诱导肺动脉高压肺血管重构的新机制

The pathogenesis of pulmonary arterial hypertention has not been fully elucidated, it is of great significance to explore a new physiopathologic mechanism of PAH in a new perspective. It is reported that pulmonary arterial smooth muscle cells senescence participated in the vascular remodeling of chronic obstructive pulmonary disease(COPD), but its molecular mechanism is not clear. And we found that hypoxia promoted the process of pulmonary arterial smooth muscle cell senescence in our preliminary experiment, and Il-6 of senescence cells secreting is related to vascular remodlling in PAH. The objective of this study was to confirm the important role of PASMCs senescence in hypoxia-induced vascular remodeling of pulmonary arterial hypertention, and verified the upsream regulatory mechanism of the mTOR/S6K1 in a hypoxia activation state promoting PASMCs senescence. What’s more, to reveal the scientific hypothesis of senescence-associated secretory phenotype (SASP) of PASMCs senescence promoting the cell proliferation, then promoting the vascular remodeling of PAH. We take the new physiopathologic mechanism about PASMCs senescence as the entry point, to reveal its effect on the vascular remodeling of pulmonary arterial hypertention, and through this way, we will provide a new thought of the pathogenesis of PAH and finding new pulmonary arterial hypertension drugs.

肺动脉高压（PAH）的发病机制尚未完全阐明，从新的视角探讨PAH病理生理机制具有重要意义。有文献报道肺动脉平滑肌细胞（PASMCs）衰老参与慢性阻塞性肺疾病肺血管重构，但具体机制不明。我们预实验发现，低氧可显著促进PASMCs衰老，同时衰老的PASMCs分泌IL-6与PAH肺血管重构有关。本项目拟通过细胞培养、在体动物实验证明PASMCs衰老在低氧诱导PAH肺血管重构中的重要作用，并进一步验证活化的mTOR/S6K1通路对PASMCs衰老的上游调控途径，以及衰老PASMCs分泌IL-6促进PASMCs增殖，导致PAH肺血管重构的科学假说。本研究以PASMCs衰老可能是肺血管重构一种新的病理生理机制为切入点，揭示其对低氧诱导PAH肺血管重构的影响，将为PAH发病机制研究及寻找新型抗肺动脉高压药物提供新思路。

肺高压（PH）的发病机制尚未完全阐明，从新的视角探讨 PH 病理生理机制具有重要意义。有文献报道肺动脉平滑肌细胞（PASMCs）衰老参与慢性阻塞性肺疾病肺血管重构，但具体机制不明。我们实验发现，低氧可显著促进 PASMCs 衰老，衰老的 PASMCs 可旁分泌 IL-6 促进 PAH 肺血管重构肺动脉平滑肌细胞增殖。我们通过细胞培养、在体动物实验证明 PASMCs 衰老在低氧诱导 PH 肺血管重构中起着重要作用，衰老 PASMCs 可旁分泌 IL-6 促进 PH 肺血管重构与 PASMCs 增殖，并进一步证实活化的 mTOR/S6K1 通路对 PASMCs 衰老的上游调控途径。本研究以 PASMCs 衰老可能是肺血管重构一种新的病理生理机制为切入点，揭示其对低氧诱导 PASMCs 衰老进而促进PASMCs 增殖肺血管重构的作用及作用机理，将为 PH 的发病机制研究及寻找新型抗肺动脉高压药物提供新策略和新思路。