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Intermedin alleviates diabetic vascular calcification by inhibiting GLUT1 through activation of the cAMP/PKA
Ya-Rong Zhang1, Shi-Meng Liu1, Yao Chen1
1Laboratory 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.
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 IMD17-47 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.
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