title: Heart rate reduction with ivabradine promotes shear stress-dependent anti-inflammatory mechanisms in arteries.
abstract: Blood flow generates wall shear stress (WSS) which alters endothelial cell (EC) function. Low WSS promotes vascular inflammation and atherosclerosis whereas high uniform WSS is protective. Ivabradine decreases heart rate leading to altered haemodynamics. Besides its cardio-protective effects, ivabradine protects arteries from inflammation and atherosclerosis via unknown mechanisms. We hypothesised that ivabradine protects arteries by increasing WSS to reduce vascular inflammation. Hypercholesterolaemic mice were treated with ivabradine for seven weeks in drinking water or remained untreated as a control. En face immunostaining demonstrated that treatment with ivabradine reduced the expression of pro-inflammatory VCAM-1 (p<0.01) and enhanced the expression of anti-inflammatory eNOS (p<0.01) at the inner curvature of the aorta. We concluded that ivabradine alters EC physiology indirectly via modulation of flow because treatment with ivabradine had no effect in ligated carotid arteries in vivo, and did not influence the basal or TNFα-induced expression of inflammatory (VCAM-1, MCP-1) or protective (eNOS, HMOX1, KLF2, KLF4) genes in cultured EC. We therefore considered whether ivabradine can alter WSS which is a regulator of EC inflammatory activation. Computational fluid dynamics demonstrated that ivabradine treatment reduced heart rate by 20 % and enhanced WSS in the aorta. In conclusion, ivabradine treatment altered haemodynamics in the murine aorta by increasing the magnitude of shear stress. This was accompanied by induction of eNOS and suppression of VCAM-1, whereas ivabradine did not alter EC that could not respond to flow. Thus ivabradine protects arteries by altering local mechanical conditions to trigger an anti-inflammatory response.
authors.forename: Le
authors.initials: L
authors.lastname: Luong
authors.forename: Hayley
authors.initials: H
authors.lastname: Duckles
authors.forename: Torsten
authors.initials: T
authors.lastname: Schenkel
authors.forename: Marwa
authors.initials: M
authors.lastname: Mahmoud
authors.forename: Jordi L
authors.initials: JL
authors.lastname: Tremoleda
authors.forename: Marzena
authors.initials: M
authors.lastname: Wylezinska-Arridge
authors.forename: Majid
authors.initials: M
authors.lastname: Ali
authors.forename: Neil P
authors.initials: NP
authors.lastname: Bowden
authors.forename: Mari-Cruz
authors.initials: MC
authors.lastname: Villa-Uriol
authors.forename: Kim
authors.initials: K
authors.lastname: van der Heiden
authors.forename: Ruoyu
authors.initials: R
authors.lastname: Xing
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gijsen
authors.forename: Jolanda
authors.initials: J
authors.lastname: Wentzel
authors.forename: Allan
authors.initials: A
authors.lastname: Lawrie
authors.forename: Shuang
authors.initials: S
authors.lastname: Feng
authors.forename: Nadine
authors.initials: N
authors.lastname: Arnold
authors.forename: Willy
authors.initials: W
authors.lastname: Gsell
authors.forename: Angela
authors.initials: A
authors.lastname: Lungu
authors.forename: Rodney
authors.initials: R
authors.lastname: Hose
authors.forename: Tim
authors.initials: T
authors.lastname: Spencer
authors.forename: Ian
authors.initials: I
authors.lastname: Halliday
authors.forename: Victoria
authors.initials: V
authors.lastname: Ridger
authors.affiliation: Prof. Paul Evans, Department of Cardiovascular Science, Faculty of Medicine, Dentistry & Health, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK, Tel.: +44 114 271 2591, Fax: +44 114 271 1863, E-mail: paul.evans@sheffield.ac.uk.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Evans
mesh_terms: D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000502:physiology; D001167:Arteritis / Q000503:physiopathology / Q000517:prevention & control*; D001552:Benzazepines / Q000494:pharmacology*; D001696:Biomechanical Phenomena; D002317:Cardiovascular Agents / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D000077550:Ivabradine; D000090062:Kruppel-Like Factor 4; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D013314:Stress, Mechanical; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D001552:Benzazepines; D002317:Cardiovascular Agents; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D019010:Vascular Cell Adhesion Molecule-1; D000077550:Ivabradine; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse
keywords: Atherosclerosis; Inflammation; haemodynamics