title: Advanced glycation end products interfere with gastric smooth muscle contractile marker expression via the AGE/RAGE/NF-κB pathway.
abstract: Excessive production of advanced glycation end products (AGE) has been implicated in the pathogenesis of diabetic complications. Smooth muscle (SM) phenotype transition is involved in diabetes-associated gastric motility dysfunction. We investigated whether AGE interfere with gastric antral SM contractile marker expression. Sixteen Sprague-Dawley rats were randomly divided into control and streptozotocin-induced diabetic groups. Sixteen weeks after streptozotocin administration, gastric antral SM strip contractility in the groups were measured. The gastric tissue expression of AGE was tested. Primary cultured gastric smooth muscle cells (SMCs) were used in complementary in vitro studies. In the presence and absence of AGE, SMCs were transfected with myocardin plasmid or treated with nuclear factor-κB (NF-κB) inhibitor or anti-RAGE antibody. Diabetic rats showed weakness of SM strip contractility and decreased expression of SM contractile marker genes (myosin heavy chains [MHC], α-actin, calponin) as compared with the control group. Gastric antral SM layer Nε-(carboxymethyl) lysine (CML) level, the major AGE compound, were increased in the diabetic rats. AGE downregulated SM contractile markers and myocardin expression in a concentration-dependent manner. Myocardin overexpression prevented these results. AGE treatment activated NF-κB in SMCs. The NF-κB inhibitor BAY 11-7082 and anti-RAGE antibody blocked the effects of AGE on myocardin downregulation. AGE may induce the development of gastric dysmotility by downregulating SM contractile proteins and myocardin expression via the AGE/RAGE/NF-κB pathway.
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, No. 300 of Guangzhou Road, Nanjing, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Yu
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, No. 300 of Guangzhou Road, Nanjing, China.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, No. 300 of Guangzhou Road, Nanjing, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, No. 300 of Guangzhou Road, Nanjing, China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Xiong
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, No. 300 of Guangzhou Road, Nanjing, China. Electronic address: linlin9100@aliyun.com.
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005746:Gastric Emptying; D015870:Gene Expression / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011706:Pyloric Antrum / Q000378:metabolism / Q000503:physiopathology; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D000096985:Calponins; D000099251:Myocardin
chemical_list: D000199:Actins; D015415:Biomarkers; D002135:Calcium-Binding Proteins; D017127:Glycation End Products, Advanced; D008840:Microfilament Proteins; D018995:Myosin Heavy Chains; D016328:NF-kappa B; D009687:Nuclear Proteins; D000067759:Receptor for Advanced Glycation End Products; D015534:Trans-Activators; D000096985:Calponins; D000099251:Myocardin; C000593874:Ager protein, rat
keywords: Age; Gastric motility; Rage; SMCs; Smooth muscle contractile marker