Reduction of endoplasmic reticulum stress through AMPK activation mediates vascular benefits of GLP-1R agonist exenatide against hyperhomocysteinemia
Refereed conference paper presented and published in conference proceedings


摘要Aims: Hyperhomocysteinemia (HHcy) is an independent risk factor for both cardiovascular diseases (CVDs) and type 2 diabetes mellitus (T2DM). Homocysteine (Hcy)-induced endoplasmic reticulum (ER) stress injures endothelial cells, resulting in endothelial dysfunction. Glucagon-like peptide 1 (GLP-1) analogue exenatide is recognized to ameliorate ER stress but its detailed mechanism remains debated. Therefore, the current investigation focused on how exenatide could lower ER stress in endothelial cells against HHcy.

Methods: Isolated aortae of wild-type rats and mice, and circumflex arteries of swine were pre-treated with exendin-4 (Ex4, a form of exenatide), followed by the acute impairment of Hcy (300 μmol/L). High methionine Low Folate (HMLF) dietinduced HHcy mice were subjected to chronic Ex4 injection (1nmol/kg) subcutaneously for 4 weeks. Vascular reactivity of arteries was assessed either by organ bath or myograph, depending on the artery size. The reactive oxygen species (ROS) level in arteries was measured by both confocal microscopy of dihydroethidium (DHE) staining and lucigenin-enhanced chemiluminescence approach. Protein and mRNA expression levels of the signaling pathway were respectively determined by Western blotting and RT-PCR in human umbilical vein endothelial cells (HUVECs) and diet-induced HHcy mice.

Results: Ex4 treatment improved endothelial function in both acutely and chronically impaired arteries. Ex4 downregulated the levels of ER stress markers such as phosphorylated eIF2α, ATF6 and spliced XBP-1. In addition, exenatide was shown to improve proper protein folding in ER to limit Hcy-induced ER stress, via the activation of AMP-activated protein kinase (AMPK).
著者CHENG Chak Kwong, LAU Chi Wai, TIAN Xiaoyu, HUANG Yu
會議地點Shanghai, China
頁次66 - 66

上次更新時間 2018-19-12 於 14:37