Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing 100083, China.
Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing 100083, China.
Aging (Albany NY). 2020 Mar 31;12(7):5651-5674. doi: 10.18632/aging.102934.
Vascular calcification is a common phenomenon in older adults. Intermedin (IMD) is a cardiovascular bioactive peptide inhibiting vascular calcification. In this study, we aimed to investigate whether IMD attenuates aging-associated vascular calcification. Vascular calcification was induced by vitamin D3 plus nicotine (VDN) in young and old rats. The calcification in aortas was more severe in old rats treated with VDN than young control rats, and IMD expression was lower. Exogenous administration of IMD significantly inhibited the calcium deposition in aortas and the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) in VDN-treated old rats. Moreover, levels of aging-related p16, p21 and β-galactosidase were all greatly decreased by IMD. These results were further confirmed in rat and human VSMCs . In addition, -deficient mouse VSMCs showed senescence features coinciding with osteogenic transition as compared with wild-type mouse VSMCs. Mechanistically, IMD significantly increased the expression of the anti-aging factor sirtuin 1 (sirt1); the inhibitory effects of IMD on calcification and senescence were blocked by knockdown. Furthermore, preincubation with inhibitors of PI3K, AMPK or PKA efficiently blunted the upregulatory effect of IMD on sirt1. Consequently, IMD could attenuate aging-associated vascular calcification by upregulating sirt1 via activating PI3K/Akt, AMPK and cAMP/PKA signaling.
血管钙化是老年人的一种常见现象。中介素（IMD）是一种抑制血管钙化的心血管生物活性肽。在这项研究中，我们旨在研究 IMD 是否可以减轻与衰老相关的血管钙化。用维生素 D3 和尼古丁（VDN）在年轻和老年大鼠中诱导血管钙化。与年轻对照组大鼠相比，VDN 处理的老年大鼠的主动脉钙化更严重，IMD 表达水平更低。外源性给予 IMD 可显著抑制 VDN 处理的老年大鼠主动脉中的钙沉积和血管平滑肌细胞（VSMC）的成骨转化。此外，IMD 还大大降低了与衰老相关的 p16、p21 和 β-半乳糖苷酶的水平。这些结果在大鼠和人 VSMC 中得到了进一步证实。此外，与野生型小鼠 VSMC 相比，-缺陷型小鼠 VSMC 表现出衰老特征，同时伴有成骨转化。在机制上，IMD 显著增加了抗衰老因子沉默调节蛋白 1（sirt1）的表达；通过 敲低，IMD 对钙化和衰老的抑制作用被阻断。此外，PI3K、AMPK 或 PKA 的抑制剂预处理可有效削弱 IMD 对 sirt1 的上调作用。因此，IMD 可通过激活 PI3K/Akt、AMPK 和 cAMP/PKA 信号通路上调 sirt1，从而减轻与衰老相关的血管钙化。
