| Title | Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP-1 receptor-dependent manner |
| Authors | Wei, Rui Ma, Shifeng Wang, Chen Ke, Jing Yang, Jin Li, Weihong Liu, Ye Hou, Wenfang Feng, Xinheng Wang, Guang Hong, Tianpei |
| Affiliation | Peking Univ, Hosp 3, Dept Endocrinol & Metab, 49 N Garden Rd, Beijing 100191, Peoples R China. Peking Univ, Hosp 3, Dept Cardiol, Beijing 100871, Peoples R China. |
| Keywords | AMP-activated protein kinase endothelial nitric oxide synthase coronary flow velocity reserve exenatide glucagon-like peptide-1 human umbilical vein endothelial cells type 2 diabetes mellitus GLUCAGON-LIKE PEPTIDE-1 NITRIC-OXIDE SYNTHASE CORONARY FLOW VELOCITY GTP-CYCLOHYDROLASE-I DIABETES-MELLITUS DOPPLER-ECHOCARDIOGRAPHY NONINVASIVE ASSESSMENT ARTERY-DISEASE TETRAHYDROBIOPTERIN RESERVE |
| Issue Date | 2016 |
| Publisher | AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM |
| Citation | AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM.2016,310(11),E947-E957. |
| Abstract | Glucagon-like peptide-1 (GLP-1) may have direct favorable effects on cardiovascular system. The aim of this study was to investigate the effects of the GLP-1 analog exenatide on improving coronary endothelial function in patients with type 2 diabetes and to investigate the underlying mechanisms. The newly diagnosed type 2 diabetic subjects were enrolled and given either lifestyle intervention or lifestyle intervention plus exenatide treatment. After 12-wk treatment, coronary flow velocity reserve (CFVR), an important indicator of coronary endothelial function, was improved significantly, and serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were remarkably decreased in the exenatide treatment group compared with the baseline and the control group. Notably, CFVR was correlated inversely with hemoglobin A(1c) (Hb A(1c)) and positively with high-density lipoprotein cholesterol (HDL-C). In human umbilical vein endothelial cells, exendin-4 (a form of exenatide) significantly increased NO production, endothelial NO synthase (eNOS) phosphorylation, and GTP cyclohydrolase 1 (GTPCH1) level in a dose-dependent manner. The GLP-1 receptor (GLP-1R) antagonist exendin (9-39) or GLP-1R siRNA, adenylyl cyclase inhibitor SQ-22536, AMPK inhibitor compound C, and PI3K inhibitor LY-294002 abolished the effects of exendin-4. Furthermore, exendin-4 reversed homocysteine-induced endothelial dysfunction by decreasing sICAM-1 and reactive oxygen species (ROS) levels and upregulating NO production and eNOS phosphorylation. Likewise, exendin (9 -39) diminished the protective effects of exendin-4 on the homocysteine-induced endothelial dysfunction. In conclusion, exenatide significantly improves coronary endothelial function in patients with newly diagnosed type 2 diabetes. The effect may be mediated through activation of AMPK/PI3K-Akt/eNOS pathway via a GLP-1R/cAMP-dependent mechanism. |
| URI | http://hdl.handle.net/20.500.11897/434148 |
| ISSN | 0193-1849 |
| DOI | 10.1152/ajpendo.00400.2015 |
| Indexed | SCI(E) PubMed |
| Appears in Collections: | 第三医院 |
