Hyperhomocysteinemia (HHcy) is a risk factor for higher mortality in type 2 diabetic patients. HHcy induces endothelial dysfunction, which precedes overt hyperglycemia in type 2 diabetic patients. In addition, endothelial dysfunction predisposes diabetic patients to cardiovascular disorders, such as atherosclerotic cardiovascular diseases and retinopathy. HHcy induces oxidative stress and endoplasmic reticulum (ER) stress to impair endothelial cells. GLP-1 agonist exendin-4 was shown to attenuate ER stress in endothelial cells although detailed mechanism remains elusive. The current study intends to reveal the beneficial effects of exendin-4 on HHcy-impaired endothelial cells.
HHcy was induced by feeding C57BL/6 mice a high methionine low folate diet for 12 weeks. To assess endothelial function, mouse aortae and mesenteric arteries were mounted on wire myograph to determine acetylcholine-induced endothelium-dependent relaxations (EDRs). OGTT and ITT were conducted to study in vivo glucose metabolism. Dihydroethidium staining and lucigenin-enhanced chemiluminescence were used to measure ROS production. The ER stress markers expression was measured by biochemical assays. The role of ER chaperone was studied by adenoviral overexpression and siRNA-mediated knockdown.
A 4-week subcutaneous injection of exendin-4 significantly improved glucose tolerance, insulin sensitivity and EDRs in arteries of diet-induced HHcy mice. Exendin-4 inhibited ROS production and ER stress markers expression in mouse aortae and human endothelial cells. Such inhibitions were ablated by compound C, an AMPK inhibitor. By AMPK activation, exendin-4 up-regulated endothelial expression of ER oxidoreductase (ERO1α), an ER chaperone. In short, through AMPK-dependent upregulation of ERO1α in endothelial cells, GLP-1 agonist exendin-4 lowers HHcy-induced ER stress and oxidative stress to restore endothelial function.
C. Cheng: None. J. Luo: None. C. Lau: None. X. Tian: None. Y. Huang: None.
Health and Medical Research Fund (05162906); Early Career Scheme (24122318); Hong Kong Research Grants Council (14112919); Collaborative Research Fund (C4024-16W)