Heart rate reduction with ivabradine promotes shear stress-dependent anti-inflammatory mechanisms in arteries

LUONG, L., DUCKLES, H., SCHENKEL, Torsten, MAHMOUD, M., TREMOLEDA, J. L., WYLEZINSKA-ARRIDGE, M., ALI, M., BOWDEN, N. P., VILLA-URIOL, M.-C., VAN DER HEIDEN, K., XING, R., GIJSEN, F. J., WENTZEL, J., LAWRIE, A., FENG, S., ARNOLD, N., GSELL, W., LUNGU, A., HOSE, R., SPENCER, Timothy, HALLIDAY, Ian, RIDGER, V. and EVANS, P. C. (2016). Heart rate reduction with ivabradine promotes shear stress-dependent anti-inflammatory mechanisms in arteries. Thrombosis and Haemostasis, 116 (1), 181-190.

[img]
Preview
PDF
Schenkel et al - Ivabradine TH resubmission-2.pdf - Accepted Version
All rights reserved.

Download (1MB) | Preview
Official URL: https://th.schattauer.de/contents/archive/issue/23...
Link to published version:: https://doi.org/10.1160/TH16-03-0214
Related URLs:

    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.

    Item Type: Article
    Research Institute, Centre or Group - Does NOT include content added after October 2018: Materials and Engineering Research Institute > Polymers Nanocomposites and Modelling Research Centre > Polymers, Composites and Spectroscopy Group
    Identification Number: https://doi.org/10.1160/TH16-03-0214
    Page Range: 181-190
    Depositing User: Carmel House
    Date Deposited: 08 Sep 2016 15:22
    Last Modified: 18 Mar 2021 06:04
    URI: http://shura.shu.ac.uk/id/eprint/13342

    Actions (login required)

    View Item View Item

    Downloads

    Downloads per month over past year

    View more statistics