Colchicine inhibits vascular calcification by suppression inflammasome activation through the enhancement of the Sirt2-PP2Ac signaling pathway

Colchicine (Col) is a traditional herbal medicine derived from the plant Colchicum autumnale. With the property of anti-inflammation, Col has been demonstrated certain therapeutic effects in cardiovascular diseases (CVDs). Vascular calcification is positively related to the morbidity and mortality of CVDs. However, the specific cardiovascular conditions for which Col is effective remain unclear, particularly its impact on vascular calcification. In this study, we used high phosphate to induced calcium deposition in vascular smooth muscle cells (VSMCs), and Vitamin D3 plus nicotine or 5/6 nephrectomy along with high phosphate diet to construct vascular calcification mouse models. Our results showed that Col reduced calcium accumulation in vitro, and vascular calcification both in ex-vivo and in vivo models, which was evidenced by the Alizarin red S staining and calcium content determination. In vitro results showed that Col inhibited vascular calcification is contributed to the reduction of NLRP3 inflammasome activation through enhanced phosphorylation at Ser 5. In addition, we indicated that phosphorylation of NLRP3 is regulated by the activity of protein phosphatase 2Ac (PP2Ac). Furthermore, we identified that Sirt2 as a master regulator of PP2Ac activation through regulation its acetylation at Lys 136. More importantly, we demonstrated that Col-inhibited vascular calcification is dependent on Sirt2 expression by using the Sirt2 knockout mice. We demonstrate that Col protects vascular calcification. Our study provides novel insight into the clinical application of Col. We also suggest that Sirt2 is a novel target for vascular calcification treatment, and that Col may act as an activator of Sirt2, which could be beneficial in other diseases.