Department of Cardiology, Affiliated Hospital of Jiangsu University, 212001, Zhenjiang, China.
Department of Pathology, Affiliated Hospital of Jiangsu University, 212001, Zhenjiang, China.
Acta Diabetol. 2019 Apr;56(4):457-472. doi: 10.1007/s00592-018-1273-1. Epub 2019 Jan 2.
Macrocalcification and microcalcification present different clinical risks, but the regulatory of their formation was unclear. Therefore, this study explored the underlying mechanisms of macrocalcification and microcalcification in diabetes mellitus.
Anterior tibial arteries of amputated diabetic feet were collected. According to the calcium content, patients were divided into less-calcification group and more-calcification group. And calcification morphology in plaques was observed. For further study, an in vivo mouse diabetic atherosclerosis model and an in vitro primary mouse aortic smooth muscle cell model were established. After the receptors for AGEs (RAGE) or galectin-3 were silenced, calcified nodule sizes and sortilin expression were determined. Scanning electron microscopy (SEM) was performed to detect the aggregation of matrix vesicles with the inhibition or promotion of sortilin.
Both macro- and microcalcification were found in human anterior tibial artery plaques. Macrocalcification formed after the silencing of RAGE, and microcalcification formed after the silencing of galectin-3. In the process of RAGE- or galcetin-3-induced calcification, sortilin played an important role downstream. SEM showed that sortilin promoted the aggregation of MVs in the early stage of calcification and formed larger calcified nodules.
RAGE downregulated sortilin and then transmitted microcalcification signals, whereas galectin-3 upregulated sortilin, which accelerated the aggregation of MVs in the early stage of calcification and mediated the formation of macrocalcifications, These data illustrate the progression of two calcification types and suggest sortilin as a potential target for early intervention of calcification and as an effective biomarker for the assessment of long-term clinical risk and prognosis.
大钙化和微钙化具有不同的临床风险，但它们的形成机制尚不清楚。因此，本研究探讨了糖尿病患者大钙化和微钙化形成的潜在机制。
收集截肢糖尿病足的胫骨前动脉。根据钙含量，患者分为少钙化组和多钙化组。并观察斑块内的钙化形态。为了进一步研究，建立了体内小鼠糖尿病动脉粥样硬化模型和体外原代小鼠主动脉平滑肌细胞模型。沉默 AGEs 受体（RAGE）或半乳糖凝集素-3 后，测定钙化结节大小和分选酶表达。扫描电子显微镜（SEM）用于检测基质小泡的聚集，并用分选酶的抑制剂或促进剂进行检测。
在人类胫骨前动脉斑块中发现了大钙化和微钙化。沉默 RAGE 后形成大钙化，沉默 galectin-3 后形成微钙化。在 RAGE 或 galectin-3 诱导的钙化过程中，分选酶在下游发挥重要作用。SEM 显示，分选酶促进了钙化早期 MV 的聚集，并形成了更大的钙化结节。
RAGE 下调分选酶，从而传递微钙化信号，而 galectin-3 上调分选酶，加速钙化早期 MV 的聚集，介导大钙化的形成。这些数据说明了两种钙化类型的进展，并提示分选酶可能是钙化早期干预的潜在靶点，也是评估长期临床风险和预后的有效生物标志物。
