SIRT6 protects vascular smooth muscle cells from osteogenic transdifferentiation via Runx2 in chronic kidney disease.
SIRT6 protects vascular smooth muscle cells from osteogenic transdifferentiation via Runx2 in chronic kidney disease.
复制标题
SIRT6 在慢性肾病中通过 Runx2 保护血管平滑肌细胞免于成骨转分化
DOI：
10.1172/jci150051
复制
发表时间：
2022-01-04
期刊：
影响因子：
--
通讯作者：
Huang H
中科院分区：
文献类型：
--
作者：
Li W;Feng W;Su X;Luo D;Li Z;Zhou Y;Zhu Y;Zhang M;Chen J;Liu B;Huang H
血管钙化（VC）是一种重要的病理改变，缺乏有效的治疗，死亡率高。Sirtuin 6（SIRT 6）是Sirtuin家族的成员，是一种III类组蛋白脱乙酰酶，也是一种关键的表观遗传调节因子。SIRT 6在慢性肾病（CKD）患者中具有保护作用。然而，SIRT 6在CKD患者VC中的确切作用和分子机制仍不清楚。在这里，我们证明了SIRT 6在外周血单核细胞（PBMC）和CKD伴VC患者的桡动脉组织中显著下调。SIRT 6转基因（SIRT 6-Tg）小鼠显示VC减轻，而血管平滑肌细胞特异性（VSMC特异性）SIRT 6敲除小鼠在CKD中显示严重的VC。SIRT 6通过调节Runx 2抑制VSMCs的成骨转分化。免疫共沉淀（co-IP）和免疫沉淀（IP）测定证实SIRT 6与Runx 2结合。此外，Runx 2被SIRT 6脱乙酰化，并通过输出蛋白1（XPO 1）进一步促进核输出，这反过来又导致Runx 2通过泛素-蛋白酶体系统降解。这些结果表明，SIRT 6通过抑制VSMC的成骨转分化来预防VC，因此靶向SIRT 6可能是CKD中VC的有吸引力的治疗靶点。
Vascular calcification (VC) is regarded as an important pathological change lacking effective treatment and associated with high mortality. Sirtuin 6 (SIRT6) is a member of the Sirtuin family, a class III histone deacetylase and a key epigenetic regulator. SIRT6 has a protective role in patients with chronic kidney disease (CKD). However, the exact role and molecular mechanism of SIRT6 in VC in patients with CKD remain unclear. Here, we demonstrated that SIRT6 was markedly downregulated in peripheral blood mononuclear cells (PBMCs) and in the radial artery tissue of patients with CKD with VC. SIRT6-transgenic (SIRT6-Tg) mice showed alleviated VC, while vascular smooth muscle cell–specific (VSMC-specific) SIRT6 knocked-down mice showed severe VC in CKD. SIRT6 suppressed the osteogenic transdifferentiation of VSMCs via regulation of runt-related transcription factor 2 (Runx2). Coimmunoprecipitation (co-IP) and immunoprecipitation (IP) assays confirmed that SIRT6 bound to Runx2. Moreover, Runx2 was deacetylated by SIRT6 and further promoted nuclear export via exportin 1 (XPO1), which in turn caused degradation of Runx2 through the ubiquitin-proteasome system. These results demonstrated that SIRT6 prevented VC by suppressing the osteogenic transdifferentiation of VSMCs, and as such targeting SIRT6 may be an appealing therapeutic target for VC in CKD.