Runx1 deficiency protects against adverse cardiac remodeling after myocardial infarction

McCarroll, C. S. et al. (2017) Runx1 deficiency protects against adverse cardiac remodeling after myocardial infarction. Circulation, 137(1), pp. 57-70. (doi:10.1161/CIRCULATIONAHA.117.028911) (PMID:29030345) (PMCID:PMC5757664)

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Abstract

Background: Myocardial infarction (MI) is a leading cause of heart failure and death worldwide. Preservation of contractile function and protection against adverse changes in ventricular architecture (cardiac remodeling) are key factors to limiting progression of this condition to heart failure. Consequently, new therapeutic targets are urgently required to achieve this aim. Expression of the Runx1 transcription factor is increased in adult cardiomyocytes after MI; however, the functional role of Runx1 in the heart is unknown. Methods: To address this question, we have generated a novel tamoxifen-inducible cardiomyocyte-specific Runx1-deficient mouse. Mice were subjected to MI by means of coronary artery ligation. Cardiac remodeling and contractile function were assessed extensively at the whole-heart, cardiomyocyte, and molecular levels. Results: Runx1-deficient mice were protected against adverse cardiac remodeling after MI, maintaining ventricular wall thickness and contractile function. Furthermore, these mice lacked eccentric hypertrophy, and their cardiomyocytes exhibited markedly improved calcium handling. At the mechanistic level, these effects were achieved through increased phosphorylation of phospholamban by protein kinase A and relief of sarco/endoplasmic reticulum Ca2+-ATPase inhibition. Enhanced sarco/endoplasmic reticulum Ca2+-ATPase activity in Runx1-deficient mice increased sarcoplasmic reticulum calcium content and sarcoplasmic reticulum–mediated calcium release, preserving cardiomyocyte contraction after MI. Conclusions: Our data identified Runx1 as a novel therapeutic target with translational potential to counteract the effects of adverse cardiac remodeling, thereby improving survival and quality of life among patients with MI.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nicklin, Professor Stuart and Smith, Professor Godfrey and Bell, Mrs Margaret and Blyth, Dr Karen and Hawksby, Mrs Catherine and Cameron, Professor Ewan and Nather, Katrin and Vidler, Francesca and Foote, Miss Kirsty and McBride, Dr Martin and Nixon, Mr Colin and Bradley, Ashley and Morrison, Dr Liam and Mcglynn, Miss Karen and He, Weihong and McCarroll, Dr Charlotte and Loughrey, Dr Christopher and MacKenzie, Dr Scott and Riddell, Alexandra and Elliott, Dr Elspeth and BOWMAN, Peter and Terry, Mrs Anne
Authors: McCarroll, C. S., He, W., Foote, K., Bradley, A., Mcglynn, K., Vidler, F., Nixon, C., Nather, K., Fatta, C., Riddell, A., Bowman, P., Elliott, E. B., Bell, M., Hawksby, C., MacKenzie, S. M., Morrison, L. J., Terry, A., Blyth, K., Smith, G. L., McBride, M. W., Kubin, T., Braun, T., Nicklin, S. A., Cameron, E. R., and Loughrey, C. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > School of Life Sciences
College of Medical Veterinary and Life Sciences > School of Veterinary Medicine
Journal Name:Circulation
Publisher:American Heart Association
ISSN:0009-7322
ISSN (Online):1524-4539
Published Online:13 October 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Circulation 137(1): 57-70
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
683201INVESTIGATING THE ROLE OF RUNX1 IN THE HEART POST-MYOCARDIAL INFARCTIONChristopher LoughreyMedical Research Council (MRC)MR/M021459/1RI CARDIOVASCULAR & MEDICAL SCIENCES
496651Investigating the expression and function of RUNX1 in cardiac tissue during myocardial infarctionChristopher LoughreyBritish Heart Foundation (BHF)PG/09/004RI CARDIOVASCULAR & MEDICAL SCIENCES
632341MRC Doctoral Training Grant 2013/14, 2014/15 and 2015/16Jeremy MottramMedical Research Council (MRC)MR/K501335/1III - PARASITOLOGY