MAPK/NF-κB 通路抑制剂可减轻高糖诱导的血管平滑肌细胞中 ET 受体的上调。
Inhibitors of the MAPK/ NF-κB pathway attenuate the upregulation of the ET receptor mediated by high glucose in vascular smooth muscle cells.
机构信息
Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi, 710021, China; School of Basic and Medical Sciences, Xi'an Medical University, Xi'an, Shaanxi, 710021, China.
The First Affiliated Hospital of Xi'an Medical University, Xi'an Medical University, Xi'an, Shaanxi, 710077, China.
出版信息
Peptides. 2022 Apr;150:170732. doi: 10.1016/j.peptides.2021.170732. Epub 2021 Dec 29.
BACKGROUND
Increased vascular smooth muscle cell (VSMC) endothelin type B (ET) receptor expression is involved in cardiovascular diseases. High glucose (HG) in diabetes is closely related to cardiovascular complications. Although diabetes upregulates VSMC endothelin subtype B (ET) receptors, its mechanism is still unclear. Our aim is to investigate the mechanism of HG-induced ET receptors in VSMCs.
METHODS
Rat superior mesenteric arteries (SMAs) without endothelium were cultured in medium without serum for 24 h. HG with or without mitogen-activated protein kinase (MAPK) signaling pathway inhibitors and downstream nuclear factor-kappaB (NF-κB) inhibitors was coincubated with SMAs. A sensitive myograph detected the contractile responses to sarafotoxin 6c. Western blotting and immunofluorescence staining were used to determine protein expression.
RESULTS
HG promoted the expression of VSMC ET receptors in rat SMAs and enhanced the ET receptor-induced contractile response. The results showed that HG increased vascular smooth muscle cell (VSMC) ET receptor expression and ET receptor-induced contractile responses in rat SMAs. Both extracellular signal-related kinase 1 and 2 (ERK1/2) inhibitors (U0126) and P38 inhibitors (SB203580) significantly inhibited HG-increased VSMC ET receptors. However, a C-jun terminal kinase (p-JNK) inhibitor (SP600125) did not affect HG- upregulated VSMC ET receptors. Further study showed that NF-κB using an IκB kinase inhibitor (wedelolactone) also significantly inhibited HG-increased VSMC ET receptors.
CONCLUSION
In conclusion, HG upregulated the VSMC ET receptor by activating the ERK1/2- or P38- NF-κB signaling pathway.
背景
血管平滑肌细胞（VSMC）内皮素 B（ET）受体表达增加与心血管疾病有关。糖尿病中的高血糖（HG）与心血管并发症密切相关。尽管糖尿病上调了 VSMC 内皮素 B 型（ET）受体，但其机制尚不清楚。我们的目的是研究 HG 诱导 VSMC 中 ET 受体的机制。
方法
无内皮的大鼠肠系膜动脉（SMA）在无血清培养基中培养 24 小时。将含有或不含有丝裂原活化蛋白激酶（MAPK）信号通路抑制剂和下游核因子-κB（NF-κB）抑制剂的 HG 与 SMA 共同孵育。敏感的肌描记器检测沙罗毒素 6c 引起的收缩反应。Western blot 和免疫荧光染色用于测定蛋白表达。
结果
HG 促进了大鼠 SMA 中 VSMC ET 受体的表达，并增强了 ET 受体诱导的收缩反应。结果表明，HG 增加了大鼠 SMA 中血管平滑肌细胞（VSMC）ET 受体的表达和 ET 受体诱导的收缩反应。ERK1/2 抑制剂（U0126）和 P38 抑制剂（SB203580）均显著抑制 HG 增加的 VSMC ET 受体。然而，c-Jun 末端激酶（p-JNK）抑制剂（SP600125）并不影响 HG 上调的 VSMC ET 受体。进一步的研究表明，NF-κB 使用 IκB 激酶抑制剂（wedelolactone）也显著抑制 HG 增加的 VSMC ET 受体。
结论
总之，HG 通过激活 ERK1/2 或 P38-NF-κB 信号通路上调 VSMC ET 受体。
Zotero 插件