title: Nicorandil attenuates cyclic strain-induced endothelin-1 expression via the induction of activating transcription factor 3 in human umbilical vein endothelial cells.
abstract: Nicorandil is an adenosine triphosphate-sensitive potassium channel opener that combines an organic nitrate and a nicotinamide group which respectively confer to nicorandil the additional properties of being a nitric oxide (NO) donor and antioxidant; it also induces vasodilation, decreases the blood pressure, and protects the heart. However, the intracellular mechanism of nicorandil remains to be delineated. The aims of this study were to test the hypothesis that nicorandil alters strain-induced endothelin-1 secretion and NO production, and to identify the putative underlying signaling pathways in human umbilical vein endothelial cells (HUVECs). Cultured HUVECs were exposed to cyclic strain in the presence of nicorandil; endothelin-1 expression was examined by reverse-transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay. Activation of extracellular signal-regulated protein kinase (ERK), endothelial NO synthase (eNOS), and activating transcription factor (ATF)-3 was assessed by Western blot analysis. We show that nicorandil inhibited strain-induced endothelin-1 expression. Nicorandil also inhibited strain-increased reactive oxygen species formation and ERK phosphorylation. On the contrary, NO production, eNOS phosphorylation, and ATF3 expression were enhanced by nicorandil; however, L-NAME (an inhibitor of eNOS) and LY294002 (an inhibitor of phosphatidylinositol 3-kinase) inhibited nicorandil-increased ATF3 expression. Moreover, treatment of HUVECs with either an NO donor (NOC18; 3,3-bis[aminoethyl]-1-hydroxy-2-oxo-1-triazene) or an ATF3 activator (MG-132; carbobenzoxy-L-leucyl-L-leucyl-L-leucinal) resulted in repression of strain-induced endothelin-1 expression. Furthermore, L-NAME, and small interfering RNA transfection of eNOS also partially attenuated the inhibitory effect of nicorandil on strain-induced endothelin-1 expression. We demonstrate for the first time that nicorandil inhibits strain-induced endothelin-1 secretion via an increase in NO and upregulation of ATF3 in HUVECs. This study provides important new insights into the molecular pathways that may contribute to the beneficial effects of nicorandil in the cardiovascular system.
authors.affiliation: Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC.
authors.forename: Hung-Hsing
authors.initials: HH
authors.lastname: Chao
authors.forename: Hong-Jye
authors.initials: HJ
authors.lastname: Hong
authors.forename: Li-Chin
authors.initials: LC
authors.lastname: Sung
authors.forename: Jin-Jer
authors.initials: JJ
authors.lastname: Chen
authors.forename: Tzu-Hurng
authors.initials: TH
authors.lastname: Cheng
authors.forename: Ju-Chi
authors.initials: JC
authors.lastname: Liu
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics* / Q000378:metabolism; D019332:Endothelin-1 / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D020108:Nicorandil / Q000494:pharmacology*; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013314:Stress, Mechanical; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: D051700:Activating Transcription Factor 3; D019332:Endothelin-1; D017382:Reactive Oxygen Species; D020108:Nicorandil; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D048049:Extracellular Signal-Regulated MAP Kinases