Melatonin alleviates vascular calcification and ageing through exosomal miR-204/miR-211 cluster in a paracrine manner
Melatonin alleviates vascular calcification and ageing through exosomal miR-204/miR-211 cluster in a paracrine manner
复制标题
褪黑素通过外泌体 miR-204/miR-211 簇以旁分泌方式减轻血管钙化和衰老
DOI：
10.1111/jpi.12631
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发表时间：
2020-04-01
影响因子：
10.3
通讯作者：
Yuan, Ling-Qing
中科院分区：
文献类型：
--
作者：
Xu, Feng;Zhong, Jia-Yu;Yuan, Ling-Qing
在患有动脉粥样硬化、高血压和糖尿病的老年人中，血管钙化和衰老现象普遍存在。褪黑激素 (MT) 已被证明会影响心血管系统。在这项研究中，我们证明了 MT 可以减轻血管钙化和衰老，以及相关的潜在机制。我们发现，MT 以 MT 膜受体依赖性方式减弱血管平滑肌细胞 (VSMC) 的成骨分化和衰老。此外，从用MT处理的VSMC或钙化血管平滑肌细胞（CVSMC）中分离的外泌体可以被VSMC摄取，并分别减弱VSMC或CVSMC的成骨分化和衰老。此外，我们使用来自MT处理的VSMC的条件培养基和Transwell实验来证实MT处理的VSMC分泌的外泌体通过旁分泌机制减弱了VSMC的成骨分化和衰老。我们还发现外泌体 miR-204/miR-211 介导 VSMC 分泌的外泌体的旁分泌作用。这两个 miR 的潜在靶标是 BMP2。此外，MT 治疗减轻了 5/6 肾切除加高磷酸盐饮食治疗 (5/6 NTP) 小鼠的血管钙化和衰老，而这些效应被 GW4869 部分逆转。通过体内荧光图像检测，源自 MT 处理的 VSMC 的外泌体被内化到小鼠动脉中，这些外泌体减少了 5/6 NTP 小鼠的血管钙化和衰老，但这两种作用在很大程度上被外泌体 miR-204 或 miR-211 的抑制所消除。总之，我们目前的研究表明，来自 MT 处理的 VSMC 的外泌体可以通过外泌体 miR-204/miR-211 以旁分泌方式减轻血管钙化和衰老。
In the elderly with atherosclerosis, hypertension and diabetes, vascular calcification and ageing are ubiquitous. Melatonin (MT) has been demonstrated to impact the cardiovascular system. In this study, we have shown that MT alleviates vascular calcification and ageing, and the underlying mechanism involved. We found that both osteogenic differentiation and senescence of vascular smooth muscle cells (VSMCs) were attenuated by MT in a MT membrane receptor-dependent manner. Moreover, exosomes isolated from VSMCs or calcifying vascular smooth muscle cells (CVSMCs) treated with MT could be uptaken by VSMCs and attenuated the osteogenic differentiation and senescence of VSMCs or CVSMCs, respectively. Moreover, we used conditional medium from MT-treated VSMCs and Transwell assay to confirm exosomes secreted by MT-treated VSMCs attenuated the osteogenic differentiation and senescence of VSMCs through paracrine mechanism. We also found exosomal miR-204/miR-211 mediated the paracrine effect of exosomes secreted by VSMCs. A potential target of these two miRs was revealed to be BMP2. Furthermore, treatment of MT alleviated vascular calcification and ageing in 5/6-nephrectomy plus high-phosphate diet-treated (5/6 NTP) mice, while these effects were partially reversed by GW4869. Exosomes derived from MT-treated VSMCs were internalised into mouse artery detected by in vivo fluorescence image, and these exosomes reduced vascular calcification and ageing of 5/6 NTP mice, but both effects were largely abolished by inhibition of exosomal miR-204 or miR-211. In summary, our present study revealed that exosomes from MT-treated VSMCs could attenuate vascular calcification and ageing in a paracrine manner through an exosomal miR-204/miR-211.