title: Effects of glucagon-like peptide-1 on advanced glycation endproduct-induced aortic endothelial dysfunction in streptozotocin-induced diabetic rats: possible roles of Rho kinase- and AMP kinase-mediated nuclear factor κB signaling pathways.
abstract: Interaction between advanced glycation endproducts (AGEs) and receptor for AGEs (RAGE) as well as downstream pathways leads to vascular endothelial dysfunction in diabetes. Glucagon-like peptide-1 (GLP-1) has been reported to attenuate endothelial dysfunction in the models of atherosclerosis. However, whether GLP-1 exerts protective effects on aortic endothelium in diabetic animal model and the underlying mechanisms are still not well defined. Experimental diabetes was induced through administration with combination of high-fat diet and intraperitoneal injection of streptozotocin. Rats were randomly divided into four groups, including controls, diabetes, diabetes + sitagliptin (30 mg/kg/day), diabetes + exenatide (3 μg/kg/12 h). Eventually, endothelial damage, markers of inflammation and oxidative stress, were measured. After 12 weeks administration, diabetic rats received sitagliptin and exenatide showed significant elevation of serum NO level and reduction of ET-1 as well as inflammatory cytokines levels. Moreover, sitagliptin and exenatide significantly inhibited aortic oxidative stress level and improved aortic endothelial function in diabetic rats. Importantly, these drugs inhibited the protein expression level in AGE/RAGE-induced RhoA/ROCK/NF-κB/IκBα signaling pathways and activated AMPK in diabetic aorta. Finally, the target proteins of p-eNOS, iNOS, and ET-1, which reflect endothelial function, were also changed by these drugs. Our present study indicates that sitagliptin and exenatide administrations can improve endothelial function in diabetic aorta. Of note, RAGE/RhoA/ROCK and AMPK mediated NF-κB signaling pathways may be the intervention targets of these drugs to protect aortic endothelium.
authors.affiliation: Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China.|Laboratory of Molecular Biology, Department of Biochemistry, Anhui Medical University, 81 Meishan Road, Hefei, Zip code: 230032, Anhui Province, China.|Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
authors.forename: Song-Tao
authors.initials: ST
authors.lastname: Tang
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
authors.forename: Qiu
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Geriatrics, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
authors.forename: Hai-Qin
authors.initials: HQ
authors.lastname: Tang
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
authors.forename: Chang-Jiang
authors.initials: CJ
authors.lastname: Wang
authors.affiliation: Laboratory of Molecular Biology, Department of Biochemistry, Anhui Medical University, 81 Meishan Road, Hefei, Zip code: 230032, Anhui Province, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Su
authors.affiliation: Laboratory of Molecular Biology, Department of Biochemistry, Anhui Medical University, 81 Meishan Road, Hefei, Zip code: 230032, Anhui Province, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Laboratory of Molecular Biology, Department of Biochemistry, Anhui Medical University, 81 Meishan Road, Hefei, Zip code: 230032, Anhui Province, China. aydzhq@126.com.
authors.forename: Hua-Qing
authors.initials: HQ
authors.lastname: Zhu
authors.affiliation: Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China. aydesm-1@163.com.|Laboratory of Molecular Biology, Department of Biochemistry, Anhui Medical University, 81 Meishan Road, Hefei, Zip code: 230032, Anhui Province, China. aydesm-1@163.com.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D059305:Diet, High-Fat; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D054795:Incretins / Q000494:pharmacology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000097:blood; D018384:Oxidative Stress / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000068900:Sitagliptin Phosphate / Q000494:pharmacology; D014688:Venoms / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D017127:Glycation End Products, Advanced; D054795:Incretins; D016328:NF-kappa B; D010455:Peptides; D017382:Reactive Oxygen Species; D014688:Venoms; D009569:Nitric Oxide; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D054460:rho-Associated Kinases; D000263:Adenylate Kinase; D000068900:Sitagliptin Phosphate
keywords: Advanced glycation endproducts; Endothelial function; Glucagon-like peptide-1; Nuclear factor κB