GDF11经自噬途径调控平滑肌细胞衰老相关分泌表型对血管老化的影响及机制研究

Senescence-associated secretory phenotype (SASP) is involved in the pathology of vascular aging. Autophagy is one of the mechanisms of SASP. The present study has found that defective autophagy in smooth muscle cells accelerates vascular aging via enhancing SASP expression. In addition, plasma levels of growth differentiation factor 11 (GDF11) have been shown to decrease in the patients with vascular aging. Importantly, exogenous GDF11 increases autophagy in smooth muscle cells and delays vascular aging. The latest studies prove that GATA4, a transcription factor of SASP, is degraded by SQSTM1-mediated autophagy and SASP inhibition delay the aging process in cells and organs. Thus, it is hypothesized that GDF11 may accelerate the degradation of GATA4 by autophagy induction, inhibiting SASP expression in smooth muscle cells and slowing the aging process of vessels. The present study is designed to confirm the anti-vascular aging effect of GDF11 in both patients and physiological and pathological mouse models. The specific knock-out mice will be used to determine increasing autophagy is the key mechanism of delaying vascular aging by GDF11 and the detailed molecular mechanism will be illustrated by interfering target gene, thus providing a new strategy for the prevention and treatment of vascular aging.

平滑肌细胞衰老相关分泌表型（SASP）参与血管老化结构重构，而自噬是SASP重要的调控机制。我们前期研究发现：平滑肌细胞自噬水平降低可通过增强SASP表达而促进血管老化；血管老化患者血浆生长分化因子11（GDF11）水平降低，而外源性GDF11可上调平滑肌细胞自噬水平并延缓血管老化。最新研究提示：SASP转录因子GATA4可经SQSTM1介导的自噬进行降解；抑制细胞SASP可有效延缓组织器官老化。据此我们提出科学假说：GDF11可能通过增强自噬加速GATA4降解，从而抑制平滑肌细胞SASP表达，延缓血管老化。本研究拟通过观察血管老化患者相关指标、构建血管老化和平滑肌细胞特异性自噬基因敲除小鼠模型，明确上调自噬为GDF11延缓血管老化的关键途径；利用靶基因干预等方法，阐明GDF11调控自噬挥发抗血管老化的具体分子机制。本项目的实施将为临床防治血管老化提供新靶点和新策略。

平滑肌细胞衰老相关分泌表型（SASP）参与血管老化结构重构，而自噬是SASP重要的调控机制。我们的研究发现：平滑肌细胞自噬水平降低可通过增强SASP表达而促进血管老化；血管老化患者血浆生长分化因子11（GDF11）水平降低，而外源性GDF11可上调平滑肌细胞自噬水平并延缓血管老化。在动物模型和细胞水平上发现，GDF11改善血管内皮依赖性舒张并减弱Ang II诱导的血管重塑；GDF11通过抑制VSMC衰老减轻Ang II诱导的血管老化；GDF11通过抑制MMP从而改善平滑肌细胞衰老，并抑制Ang II诱导的ROS生成。在分子机制上，GDF11通过自噬途径调节ROS-MMP轴参与抗血管老化。本研究证实临床患者血浆中GDF11水平与血管衰老明显负相关，外源性补充GDF11可以延缓小鼠血管老化，并证实自噬为GDF11发挥延缓衰老的关键环节。此外，我们进一步研究发现：自噬激动剂二甲双胍具有抑制平滑肌细胞衰老分泌表型改善血管老化。该研究发现将提供对血管老化进行临床干预的理论依据。