miRNA-34a 诱导的衰老相关分泌表型(SASP)有利于血管平滑肌细胞钙化。
The microRNA-34a-Induced Senescence-Associated Secretory Phenotype (SASP) Favors Vascular Smooth Muscle Cells Calcification.
机构信息
Unit of Experimental Cardio-Oncology and Cardiovascular Aging, Centro Cardiologico Monzino-IRCCS, 20138 Milan, Italy.
Unit of Biostatistics, Centro Cardiologico Monzino-IRCCS, 20138 Milan, Italy.
出版信息
Int J Mol Sci. 2020 Jun 23;21(12):4454. doi: 10.3390/ijms21124454.
The senescence of vascular smooth muscle cells (VSMCs), characterized by the acquisition of senescence-associated secretory phenotype (SASP), is relevant for VSMCs osteoblastic differentiation and vascular calcification (VC). MicroRNA-34a (miR-34a) is a driver of such phenomena and could play a role in vascular inflammaging. Herein, we analyzed the relationship between miR-34a and the prototypical SASP component IL6 in in vitro and in vivo models. miR-34a and IL6 levels increased and positively correlated in aortas of 21 months-old male C57BL/6J mice and in human aortic smooth muscle cells (HASMCs) isolated from donors of different age and undergone senescence. Lentiviral overexpression of miR-34a in HASMCs enhanced IL6 secretion. HASMCs senescence and calcification accelerated after exposure to conditioned medium of miR-34a-overexpressing cells. Analysis of miR-34a-induced secretome revealed enhancement of several pro-inflammatory cytokines and chemokines, including IL6, pro-senescent growth factors and matrix-degrading molecules. Moreover, induction of aortas medial calcification and concomitant IL6 expression, with an overdose of vitamin D, was reduced in male C57BL/6J mice. Finally, a positive correlation was observed between circulating miR-34a and IL6 in healthy subjects of 20-90 years. Hence, the vascular age-associated miR-34a promotes VSMCs SASP activation and contributes to arterial inflammation and dysfunctions such as VC.
血管平滑肌细胞(VSMC)衰老的特征是获得衰老相关分泌表型(SASP),这与 VSMC 成骨样分化和血管钙化(VC)有关。微小 RNA-34a(miR-34a)是这些现象的驱动因素,可能在血管炎症中发挥作用。在此,我们分析了 miR-34a 与体外和体内模型中典型的 SASP 成分 IL6 之间的关系。21 月龄雄性 C57BL/6J 小鼠的主动脉和从不同年龄供体分离并经历衰老的人主动脉平滑肌细胞(HASMC)中 miR-34a 和 IL6 水平增加且呈正相关。在 HASMC 中过表达 miR-34a 可增强 IL6 分泌。暴露于过表达 miR-34a 细胞的条件培养基后,HASMCs 衰老和钙化加速。对 miR-34a 诱导的分泌组进行分析表明,包括 IL6 在内的几种促炎细胞因子和趋化因子、促衰老生长因子和基质降解分子的表达增强。此外,在雄性 C57BL/6J 小鼠中,过量维生素 D 引起的主动脉中层钙化和伴随的 IL6 表达减少。最后,在 20-90 岁的健康受试者中观察到循环 miR-34a 和 IL6 之间存在正相关。因此,与血管年龄相关的 miR-34a 促进了 VSMC 的 SASP 激活,并有助于动脉炎症和功能障碍,如 VC。