Li Shunyi, She Jianglian, Zeng Jingxin, Xie Kaiji, Luo Zichao, Su Shuwen, Chen Jun, Xian Gaopeng, Cheng Zhendong, Zhao Jing, Li Shaoping, Xu Xingbo, Xu Dingli, Tang Lan, Zhou Xuefeng, Zeng Qingchun
State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
CAS Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, China.
Oxid Med Cell Longev. 2022 Aug 17;2022:6776050. doi: 10.1155/2022/6776050. eCollection 2022.
Calcific aortic valve disease (CAVD) is a valvular disease frequently in the elderly individuals that can lead to the valve dysfunction. Osteoblastic differentiation of human aortic valve interstitial cells (HAVICs) induced by inflammation play a crucial role in CAVD pathophysiological processes. To date, no effective drugs for CAVD have been established, and new agents are urgently needed. Piericidin glycosides, obtained from a marine-derived strain, were revealed to have regulatory effects on mitochondria in previous studies. Here, we discovered that 13-hydroxypiericidin A 10---D-glucose (1→6)--D-glucoside (S18), a specific piericidin diglycoside, suppresses lipopolysaccharide- (LPS) induced inflammatory responses of HAVICs by alleviating mitochondrial stress in an interleukin (IL)-37-dependent manner. Knockdown of IL-37 by siRNA not only exaggerated LPS-induced HAVIC inflammation and mitochondrial stress but also abrogated the anti-inflammatory effect of S18 on HAVICs. Moreover, S18 alleviated aortic valve lesions in IL-37 transgenic mice of CAVD model. Microscale thermophoresis (MST) and docking analysis of five piericidin analogues suggested that diglycosides, but not monoglycosides, exert obvious IL-37-binding activity. These results indicate that S18 directly binds to IL-37 to alleviate inflammatory responses in HAVICs and aortic valve lesions in mice. Piericidin diglycoside S18 is a potential therapeutic agent to prevent the development of CAVD.
钙化性主动脉瓣疾病（CAVD）是一种常见于老年人的瓣膜疾病，可导致瓣膜功能障碍。炎症诱导的人主动脉瓣间质细胞（HAVICs）成骨分化在CAVD病理生理过程中起关键作用。迄今为止，尚未建立治疗CAVD的有效药物，迫切需要新的药物。在先前的研究中，从海洋来源的菌株中获得的杀稻瘟菌素糖苷被发现对线粒体具有调节作用。在这里，我们发现13-羟基杀稻瘟菌素A 10---D-葡萄糖（1→6）--D-葡萄糖苷（S18），一种特定的杀稻瘟菌素二糖苷，通过以白细胞介素（IL）-37依赖性方式减轻线粒体应激来抑制脂多糖（LPS）诱导的HAVICs炎症反应。用小干扰RNA（siRNA）敲低IL-37不仅会加剧LPS诱导的HAVICs炎症和线粒体应激，还会消除S18对HAVICs的抗炎作用。此外，S18减轻了CAVD模型的IL-37转基因小鼠的主动脉瓣病变。对五种杀稻瘟菌素类似物的微量热泳动（MST）和对接分析表明，二糖苷而非单糖苷具有明显的IL-37结合活性。这些结果表明，S18直接与IL-37结合，以减轻HAVICs中的炎症反应和小鼠的主动脉瓣病变。杀稻瘟菌素二糖苷S18是预防CAVD发展的潜在治疗剂。
