Department of Medicine - DIMED, University of Padova, Padova, Italy.
Veneto Institute of Molecular Medicine, Padova, Italy.
Diabetologia. 2022 Sep;65(9):1555-1568. doi: 10.1007/s00125-022-05733-2. Epub 2022 Jun 16.
AIMS/HYPOTHESIS: Ectopic calcification is a typical feature of diabetic vascular disease and resembles an accelerated ageing phenotype. We previously found an excess of myeloid calcifying cells in diabetic individuals. We herein examined molecular and cellular pathways linking atherosclerotic calcification with calcification by myeloid cells in the diabetic milieu.
We first examined the associations among coronary calcification, myeloid calcifying cell levels and mononuclear cell gene expression in a cross-sectional study of 87 participants with type 2 diabetes undergoing elective coronary angiography. Then, we undertook in vitro studies on mesenchymal stem cells and the THP-1 myeloid cell line to verify the causal relationships of the observed associations.
Coronary calcification was associated with 2.8-times-higher myeloid calcifying cell levels (p=0.037) and 50% elevated expression of the osteogenic gene RUNX2 in mononuclear cells, whereas expression of Sirtuin-7 (SIRT7) was inversely correlated with calcification. In standard differentiation assays of mesenchymal stem cells, SIRT7 knockdown activated the osteogenic program and worsened calcification, especially in the presence of high (20 mmol/l) glucose. In the myeloid cell line THP-1, SIRT7 downregulation drove a pro-calcific phenotype, whereas SIRT7 overexpression prevented high-glucose-induced calcification. Through the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, high glucose induced miR-125b-5p, which in turn targeted SIRT7 in myeloid cells and was directly associated with coronary calcification.
CONCLUSIONS/INTERPRETATION: We describe a new pathway elicited by high glucose through the JAK/STAT cascade, involving regulation of SIRT7 by miR-125b-5p and driving calcification by myeloid cells. This pathway is associated with coronary calcification in diabetic individuals and may be a target against diabetic vascular disease.
RNA sequencing data are deposited in GEO (accession number GSE193510; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE193510 ).
目的/假设：异位钙化是糖尿病血管疾病的典型特征，类似于加速衰老表型。我们之前发现糖尿病患者中髓样钙化细胞过多。本文研究了在糖尿病环境中连接动脉粥样硬化钙化和髓样细胞钙化的分子和细胞途径。
我们首先在接受选择性冠状动脉造影的 87 名 2 型糖尿病患者的横断面研究中，检查了冠状动脉钙化、髓样钙化细胞水平和单核细胞基因表达之间的关联。然后，我们在间充质干细胞和 THP-1 髓样细胞系上进行了体外研究，以验证观察到的关联的因果关系。
冠状动脉钙化与髓样钙化细胞水平高 2.8 倍（p=0.037）和单核细胞中成骨基因 RUNX2 表达升高 50%相关，而 Sirtuin-7（SIRT7）的表达与钙化呈负相关。在间充质干细胞的标准分化实验中，SIRT7 敲低激活了成骨程序并加重了钙化，尤其是在高（20 mmol/l）葡萄糖存在的情况下。在髓样细胞系 THP-1 中，SIRT7 下调驱动了促钙化表型，而 SIRT7 过表达可防止高葡萄糖诱导的钙化。通过 Janus 激酶（JAK）/信号转导和转录激活因子（STAT）途径，高葡萄糖诱导了 miR-125b-5p，其反过来靶向髓样细胞中的 SIRT7，并与冠状动脉钙化直接相关。
结论/解释：我们描述了高葡萄糖通过 JAK/STAT 级联诱导的一条新途径，涉及 miR-125b-5p 对 SIRT7 的调节和髓样细胞的钙化驱动。该途径与糖尿病个体的冠状动脉钙化有关，可能是针对糖尿病血管疾病的靶点。
RNA 测序数据已存入 GEO（注册号 GSE193510；https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE193510）。
