title: Resistin increases monolayer permeability of human coronary artery endothelial cells.
abstract: Resistin has been linked to obesity, insulin resistance, atherosclerosis, and the development of cardiovascular disease. Nevertheless, the effects and the molecular mechanisms of resistin on endothelial permeability, a key event in the development of atherosclerosis, inflammation, and vascular disease, are largely unknown. In order to determine the effect of resistin on endothelial permeability, human coronary artery endothelial cells (HCAECs) were treated with clinically relevant concentrations of resistin and the endothelial permeability was measured using the Transwell system with a Texas-Red-labeled dextran tracer. The permeability of HCAEC monolayers treated with resistin (80 ng/mL) was 51% higher than the permeability of control monolayers (P<0.05). The mRNA levels of tight junction proteins zonula occludens-1 (ZO-1) and occludin in resistin-treated cells were 37% and 42% lower, respectively, than the corresponding levels in untreated cells. The protein levels of these molecules in resistin-treated cells were significantly reduced by 35% and 37%, respectively (P<0.05), as shown by flow cytometry and Western blot analysis. Superoxide dismutase (SOD) mimetic MnTBAP effectively blocked the resistin-mediated reduction of ZO-1 and occludin levels in HCAECs. In addition, superoxide anion production was increased from 21% (untreated cells) to 55% (cells treated with 40 ng/mL resistin), and 64% (resistin, 80 mg/mL) (P<0.05). The natural antioxidant Ginkgolide A effectively inhibited resistin-induced increase in permeability and the increase in superoxide anion production in HCAECs. Furthermore, resistin treatment significantly activated p38 MAPK, but not ERK1/2. Pretreatment of HCAECs with a p38 inhibitor effectively blocked resistin-induced permeability. These results provide new evidence that resistin may contribute to the vascular lesion formation via increasing endothelial permeability through the mechanism of oxidative stress and the activation of p38 MAPK.
authors.affiliation: Molecular Surgeon Research Center, Division of Surgical Research, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, United States of American.
authors.forename: Md Saha
authors.initials: MS
authors.lastname: Jamaluddin
authors.affiliation: Molecular Surgeon Research Center, Division of Surgical Research, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, United States of American.
authors.forename: Shaoyu
authors.initials: S
authors.lastname: Yan
authors.affiliation: Molecular Surgeon Research Center, Division of Surgical Research, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, United States of American.
authors.forename: Jianming
authors.initials: J
authors.lastname: Lü
authors.affiliation: Molecular Surgeon Research Center, Division of Surgical Research, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, United States of American.
authors.forename: Zhengdong
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Molecular Surgeon Research Center, Division of Surgical Research, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, United States of American.
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Yao
authors.affiliation: Molecular Surgeon Research Center, Division of Surgical Research, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, United States of American.
authors.forename: Changyi
authors.initials: C
authors.lastname: Chen
mesh_terms: D002199:Capillary Permeability; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D020935:MAP Kinase Signaling System; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D052243:Resistin / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D062826:Zonula Occludens-1 Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C499624:RETN protein, human; D012333:RNA, Messenger; D052243:Resistin; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D013482:Superoxide Dismutase; D048051:p38 Mitogen-Activated Protein Kinases