title: Ivabradine Prevents Low Shear Stress Induced Endothelial Inflammation and Oxidative Stress via mTOR/eNOS Pathway.
abstract: Ivabradine not only reduces heart rate but has other cardiac and vascular protective effects including anti-inflammation and anti-oxidation. Since endothelial nitric oxide synthase (eNOS) is a crucial enzyme in maintaining endothelial activity, we aimed to investigate the impact of ivabradine in low shear stress (LSS) induced inflammation and endothelial injury and the role of eNOS played in it. Endothelial cells (ECs) were subjected to LSS at 2dyne/cm2, with 1 hour of ivabradine (0.04μM) or LY294002 (10μM) pre-treatment. The mRNA expression of IL-6, VCAM-1 along with eNOS were measured by QPCR. Reactive oxygen species (ROS) was detected by dihydroethidium (DHE) and DCF, and protein phosphorylation was detected by western blot. It demonstrated that ivabradine decreased LSS induced inflammation and oxidative stress in endothelial cells. Western blot showed reduced rictor and Akt-Ser473 as well as increased eNOS-Thr495 phosphorylation. However, mTORC1 pathway was only increased when LSS applied within 30 minutes. These effects were reversed by ivabradine. It would appear that ivabradine diminish ROS generation by provoking mTORC2/Akt phosphorylation and repressing mTORC1 induced eNOS-Thr495 activation. These results together suggest that LSS induced endothelial inflammation and oxidative stress are suppressed by ivabradine via mTORC2/Akt activation and mTORC1/eNOS reduction.
authors.affiliation: Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, 68# Changle Road, Nanjing, 210006, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, 68# Changle Road, Nanjing, 210006, China.
authors.forename: Junxia
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, 68# Changle Road, Nanjing, 210006, China.
authors.forename: Zhimei
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, 68# Changle Road, Nanjing, 210006, China.
authors.forename: Shaoliang
authors.initials: S
authors.lastname: Chen
mesh_terms: D001552:Benzazepines / Q000494:pharmacology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000473:pathology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D000077550:Ivabradine; D008856:Microscopy, Fluorescence; D009025:Morpholines / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013314:Stress, Mechanical; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D001552:Benzazepines; D002867:Chromones; D015850:Interleukin-6; D009025:Morpholines; D020011:Protective Agents; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; D010768:Phosphoserine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000077550:Ivabradine; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases