title: Resveratrol attenuates vascular endothelial inflammation by inducing autophagy through the cAMP signaling pathway.
abstract: Inflammation participates centrally in all stages of atherosclerosis (AS), which begins with inflammatory changes in the endothelium, characterized by expression of the adhesion molecules. Resveratrol (RSV) is a naturally occurring phytoalexin that can attenuate endothelial inflammation; however, the exact mechanisms have not been thoroughly elucidated. Autophagy refers to the normal process of cell degradation of proteins and organelles, and is protective against certain inflammatory injuries. Thus, we intended to determine the role of autophagy in the antiinflammatory effects of RSV in human umbilical vein endothelial cells (HUVECs). We found that RSV pretreatment reduced tumor necrosis factor ? (TNF/TNF?)-induced inflammation and increased MAP1LC3B2 (microtubule-associated protein 1 light chain 3 ? 2) expression and SQSTM1/p62 (sequestosome 1) degradation in a concentration-dependent manner. A bafilomycin A 1 (BafA1) challenge resulted in further accumulation of MAP1LC3B2 in HUVECs. Furthermore, autophagy inhibitors 3-methyladenine (3-MA), chloroquine as well as ATG5 and BECN1 siRNA significantly attenuated RSV-induced autophagy, which, subsequently, suppressed the downregulation of RSV-induced inflammatory factors expression. RSV also increased cAMP (cyclic adenosine monophosphate) content, the expression of PRKA (protein kinase A) and SIRT1 (sirtuin 1), as well as the activity of AMPK (AMP-activated protein kinase). RSV-induced autophagy in HUVECs was abolished in the presence of inhibitors of ADCY (adenylyl cyclase, KH7), PRKA (H-89), AMPK (compound C), or SIRT1 (nicotinamide and EX-527), as well as ADCY, PRKA, AMPK, and SIRT1 siRNA transfection, indicating that the effects of RSV on autophagy induction were dependent on cAMP, PRKA, AMPK and SIRT1. In conclusion, RSV attenuates endothelial inflammation by inducing autophagy, and the autophagy in part was mediated through the activation of the cAMP-PRKA-AMPK-SIRT1 signaling pathway.
authors.affiliation: Research Center for Nutrition and Food Safety; Institute of Military Preventive Medicine; Third Military Medical University; Chongqing Key Laboratory of Nutrition and Food Safety; Chongqing, China.
authors.forename: Ming-Liang
authors.initials: ML
authors.lastname: Chen
authors.forename: Long
authors.initials: L
authors.lastname: Yi
authors.forename: Xin
authors.initials: X
authors.lastname: Jin
authors.forename: Xin-Yu
authors.initials: XY
authors.lastname: Liang
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhou
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Qi
authors.initials: Q
authors.lastname: Xie
authors.forename: Xi
authors.initials: X
authors.lastname: Zhou
authors.forename: Hui
authors.initials: H
authors.lastname: Chang
authors.forename: Yu-Jie
authors.initials: YJ
authors.lastname: Fu
authors.forename: Jun-Dong
authors.initials: JD
authors.lastname: Zhu
authors.forename: Qian-Yong
authors.initials: QY
authors.lastname: Zhang
authors.forename: Man-Tian
authors.initials: MT
authors.lastname: Mi
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000502:physiology; D001343:Autophagy / Q000187:drug effects*; D002227:Carbazoles / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D007546:Isoquinolines / Q000494:pharmacology; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000502:physiology; D013267:Stilbenes / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014657:Vasculitis / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control
chemical_list: C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D000067956:Adenylyl Cyclase Inhibitors; D002227:Carbazoles; D007546:Isoquinolines; D013267:Stilbenes; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C025946:3-methyladenine; D000242:Cyclic AMP; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000262:Adenylyl Cyclases; D000225:Adenine; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D000077185:Resveratrol
keywords: autophagy; cAMP; endothelial cells; inflammation; resveratrol