中介素通过激活 cAMP/PKA 信号通路抑制 GLUT1 缓解糖尿病血管钙化。

Intermedin alleviates diabetic vascular calcification by inhibiting GLUT1 through activation of the cAMP/PKA signaling pathway.

机构信息

Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing, 100083, China; StateKey Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, 100083, China; Department of Pathogen Biology, School of Basic Medical Science, Peking University, Beijing, 100083, China.

Department of Pathogen Biology, School of Basic Medical Science, Peking University, Beijing, 100083, China.

出版信息

Atherosclerosis. 2023 Nov;385:117342. doi: 10.1016/j.atherosclerosis.2023.117342. Epub 2023 Oct 11.

DOI:10.1016/j.atherosclerosis.2023.117342

PMID:37879153

Abstract

BACKGROUND AND AIMS

Vascular calcification (VC) is regarded as an independent risk factor for cardiovascular events in type 2 diabetic patients. Glucose transporter 1 (GLUT1) involves VC. Intermedin/Adrenomedullin-2 (IMD/ADM2) is a cardiovascular protective peptide that can inhibit multiple disease-associated VC. However, the role and mechanism of IMD in diabetic VC remain unclear. Here, we investigated whether IMD inhibits diabetic VC by inhibiting GLUT1.

METHODS AND RESULTS

It was found that plasma IMD concentration was significantly decreased in type 2 diabetic patients and in fructose-induced diabetic rats compared with that in controls. Plasma IMD content was inversely correlated with fasting blood glucose level and VC severity. IMD alleviated VC in fructose-induced diabetic rats. Deficiency of Adm2 aggravated and Adm2 overexpression attenuated VC in high-fat diet-induced diabetic mice. In vitro, IMD mitigated high glucose-induced calcification of vascular smooth muscle cells (VSMCs). Mechanistically, IMD reduced advanced glycation end products (AGEs) content and the level of receptor for AGEs (RAGE). IMD decreased glucose transporter 1 (GLUT1) levels. The inhibitory effect of IMD on RAGE protein level was blocked by GLUT1 knockdown. GLUT1 knockdown abolished the effect of IMD on alleviating VSMC calcification. IMD receptor antagonist IMD and cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) inhibitor H89 abolished the inhibitory effects of IMD on GLUT1 and VSMC calcification.

CONCLUSIONS

These findings revealed that IMD exerted its anti-calcification effect by inhibiting GLUT1, providing a novel therapeutic target for diabetic VC.

摘要

背景与目的

血管钙化（VC）被认为是 2 型糖尿病患者心血管事件的独立危险因素。葡萄糖转运蛋白 1（GLUT1）参与 VC。中介素/肾上腺髓质素-2（IMD/ADM2）是一种心血管保护肽，可抑制多种与疾病相关的 VC。然而，IMD 在糖尿病 VC 中的作用和机制尚不清楚。在这里，我们研究了 IMD 是否通过抑制 GLUT1 来抑制糖尿病 VC。

方法和结果

研究发现，与对照组相比，2 型糖尿病患者和果糖诱导的糖尿病大鼠的血浆 IMD 浓度显著降低。血浆 IMD 含量与空腹血糖水平和 VC 严重程度呈负相关。IMD 减轻了果糖诱导的糖尿病大鼠的 VC。Adm2 缺乏加重和 Adm2 过表达减轻高脂肪饮食诱导的糖尿病小鼠的 VC。体外，IMD 减轻了高葡萄糖诱导的血管平滑肌细胞（VSMCs）钙化。在机制上，IMD 降低了晚期糖基化终产物（AGEs）含量和 AGEs 受体（RAGE）水平。IMD 降低了葡萄糖转运蛋白 1（GLUT1）水平。GLUT1 敲低阻断了 IMD 对 RAGE 蛋白水平的抑制作用。GLUT1 敲低消除了 IMD 减轻 VSMC 钙化的作用。IMD 受体拮抗剂 IMD 和环磷酸腺苷/蛋白激酶 A（cAMP/PKA）抑制剂 H89 消除了 IMD 对 GLUT1 和 VSMC 钙化的抑制作用。