Department of Vascular Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.
Department of Breast, Thyroid and Vascular Surgery, Traditional Chinese Medicine Hospital Affiliated to Southwest Medical University, Luzhou 646000, China.
J Diabetes Res. 2022 Feb 1;2022:4067812. doi: 10.1155/2022/4067812. eCollection 2022.
Systemic vascular impairment is the most common complication of diabetes. Advanced glycation end products (AGEs) can exacerbate diabetes-related vascular damage by affecting the intima and media through a variety of mechanisms. In the study, we demonstrated that AGEs and their membrane receptor RAGE could induce the differentiation of EPCs into osteoblasts under certain circumstances, thereby promoting accelerated atherosclerosis. Differentiation into osteoblasts was confirmed by positive staining for DiI-acetylated fluorescently labeled low-density lipoprotein and FITC-conjugated agglutinin. During differentiation, expression of receptor for AGE (RAGE) was significantly upregulated. This upregulation was attenuated by transfection with RAGE-targeting small interfering (si)RNA. siRNA-mediated knockdown of RAGE expression significantly inhibited the upregulation of AGE-induced calcification-related proteins, such as runt-related transcription factor 2 (RUNX2) and osteoprotegerin (OPG). Additional experiments showed that AGE induction of EPCs significantly induced ERK, p38MAPK, and JNK activation. The AGE-induced upregulation of osteoblast proteins (RUNX2 and OPG) was suppressed by treatment with a p38MAPK inhibitor (SB203580) or JNK inhibitor (SP600125), but not by treatment with an ERK inhibitor (PD98059), which indicated that AGE-induced osteoblast differentiation from EPCs may be mediated by p38MAPK and JNK signaling, but not by ERK signaling. These data suggested that AGEs may bind to RAGE on the EPC membrane to trigger differentiation into osteoblasts. The underlying mechanism appears to involve the p38MAPK and JNK1/2 pathways, but not the ERK1/2 pathway.
系统性血管损伤是糖尿病最常见的并发症。糖基化终产物（AGEs）可通过多种机制影响内膜和中膜，从而加剧与糖尿病相关的血管损伤。在研究中，我们证明在某些情况下，AGEs及其膜受体 RAGE 可诱导 EPC 分化为成骨细胞，从而促进动脉粥样硬化的加速形成。分化为成骨细胞通过 DiI-乙酰化荧光标记的低密度脂蛋白和 FITC 结合凝集素的阳性染色来证实。在分化过程中，AGE 受体（RAGE）的表达明显上调。用 RAGE 靶向小干扰（si）RNA 转染可减弱这种上调。siRNA 介导的 RAGE 表达下调显著抑制了 AGE 诱导的钙化成骨相关蛋白（如 runt 相关转录因子 2（RUNX2）和骨保护素（OPG））的上调。进一步的实验表明，AGE 诱导 EPC 明显诱导 ERK、p38MAPK 和 JNK 激活。用 p38MAPK 抑制剂（SB203580）或 JNK 抑制剂（SP600125）处理可抑制 AGE 诱导的成骨蛋白（RUNX2 和 OPG）的上调，但用 ERK 抑制剂（PD98059）处理则不能，这表明 AGE 诱导的 EPC 向成骨细胞分化可能是通过 p38MAPK 和 JNK 信号通路介导的，而不是通过 ERK 信号通路。这些数据表明，AGEs 可能与 EPC 膜上的 RAGE 结合，触发向成骨细胞的分化。其潜在机制似乎涉及 p38MAPK 和 JNK1/2 通路，但不涉及 ERK1/2 通路。
