A miR-125/Sirtuin-7 pathway drives the pro-calcific potential of myeloid cells in diabetic vascular disease,Diabetologia

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A miR-125/Sirtuin-7 pathway drives the pro-calcific potential of myeloid cells in diabetic vascular disease
Diabetologia ( IF 8.4 ) Pub Date : 2022-06-16 , DOI: 10.1007/s00125-022-05733-2
Saula Vigili de Kreutzenberg ₁ , Alessandra Giannella ₁ , Giulio Ceolotto ₁ , Elisabetta Faggin ₁ , Roberta Cappellari _{1,

2} , Marta Mazzucato ₁ , Chiara Fraccaro ₃ , Giuseppe Tarantini ₃ , Angelo Avogaro ₁ , Gian Paolo Fadini _{1,

2}

Affiliation

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.

Methods

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.

Results

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.

Data availability

RNA sequencing data are deposited in GEO (accession number GSE193510; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE193510).

Graphical abstract

中文翻译：

miR-125/Sirtuin-7 通路驱动糖尿病血管疾病中骨髓细胞的促钙化潜力

目标/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。我们之前在糖尿病患者中发现了过量的骨髓钙化细胞。我们在此研究了将动脉粥样硬化钙化与糖尿病环境中骨髓细胞钙化联系起来的分子和细胞途径。

方法

我们首先在一项横断面研究中检查了冠状动脉钙化、骨髓钙化细胞水平和单核细胞基因表达之间的关联，该研究对 87 名 2 型糖尿病患者进行了选择性冠状动脉造影。然后，我们对间充质干细胞和 THP-1 骨髓细胞系进行了体外研究，以验证观察到的关联的因果关系。

结果

冠状动脉钙化与骨髓钙化细胞水平升高 2.8 倍（p = 0.037）以及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测定中，SIRT7 敲低激活了成骨程序并恶化了钙化，特别是在高（20 mmol/l）葡萄糖存在的情况下。在骨髓细胞系 THP-1 中，SIRT7 下调可驱动促钙化表型，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) 通路，高葡萄糖诱导 miR-125b-5p，进而靶向骨髓细胞中的 SIRT7，并与冠状动脉钙化直接相关。