A novel role for the plasma membrane calcium pump (PMCA1) in cardiomyopathy and blood pressure control

Lead Research Organisation: University of Manchester
Department Name: Medical and Human Sciences

Abstract

Heart failure affects around 1 million people in the UK, patient numbers are rising rapidly and survival is similar to that of some cancers. Heart failure patients are known to die from two main causes, either pump failure or heartbeat abnormalities (arrhythmias). In addition, high blood pressure (hypertension) greatly aggravates heart failure.

Improving treatment of heart failure, which currently is highly unsatisfactory, is the main motivation for our research. We have shown that a gene called the plasma membrane calcium pump isoform 1 (PMCA1) is central to all three key features of heart failure ? pump failure, arrhythmias and hypertension. By transporting calcium out of the cell PMCA1 helps the heart muscle to relax and blood pressure to fall. Strongly supporting our approach, recent genetic studies in humans have shown that PMCA1 is key to human disease. Our programme will take these findings to the next essential level, i.e. understanding the function of PMCA1. To this end we will study mouse models in which the level of PMCA1 in the heart and vessels has been genetically modified. This programme is pivotal for understanding heart failure and hypertension and will provide information essential to the development of new treatments.

Technical Summary

Heart failure (HF) currently affects around 1 million people in the UK leading to an annual financial burden on the health services of over #1 billion, and its incidence is rising rapidly. HF has a dismal prognosis, with patients dying from progressive pump failure or ventricular arrhythmias. Hypertension, which affects around 15% of the general population, is strongly associated with heart failure with 80% of HF patients having hypertension.

PMCA1 is a member of a family of four transmembrane calcium transporters that eject calcium from the cell, but whose exact (patho)physiological function remains unknown.

We have made the unexpected finding that PMCA1 is involved in all of the central features of heart failure: cardiomyopathy, arrhythmias and hypertension:
? Our cardiomyocyte-specific PMCA1 knockout mice(PMCA1cko) develop severe cardiomyopathy with HF and lethal rhythm disorders. Rhythm disorders occur before ventricular dilatation suggesting a highly specific mechanism.
? Our heterozygote global PMCA1 knockout mice(PMCA1Ht) have raised blood pressure (homozygotes are not viable).
? Three recent genome wide association studies (White, Korean and Japanese populations) by others have identified single nucleotide polymorphisms in the PMCA1 gene as the single strongest association with blood pressure variance in humans.

It is the purpose of the present programme to determine the mechanisms underlying the role of PMCA1 in heart failure and high blood pressure at the whole animal, organ as well as at the cellular/molecular level.

To this end, we will use our tissue-specific (cardiomyocyte, vascular smooth muscle) PMCA1 knockout mice as well as state-of-the-art in vivo haemodynamic, electrophysiological, functional and molecular techniques. We have 20 years of experience with the molecular biology and (patho)physiology of the plasma membrane calcium pumps; all requisite techniques are long established in our group and we are leaders in the field. This leadership has been recognised and facilitated by MRC International Appointee and programme grant funding since 2001, which has been on PMCA4, an independent isoform of the calcium pump with entirely different functions.

This programme is at the heart of the research priorities of the MRC. Firstly, research into heart failure, ventricular arrhythmias and hypertension have been key areas of MRC funding over many years. Secondly, understanding the function of the genes underlying the genetic components of disease (physiological genomics) has been defined as a focus of the MRC (Theme 2, ?Living a long and healthy life?, ?Genetics and Disease?).

Publications

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Huang C (2016) Editorial: Ca2+ Signaling and Heart Rhythm in Frontiers in Physiology

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Mohamed TM (2013) Optimisation and validation of a high throughput screening compatible assay to identify inhibitors of the plasma membrane calcium ATPase pump--a novel therapeutic target for contraception and malaria. in Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques

 
Description A novel role for the plasma membrane calcium pump (PMCA1) in cardiomyopathy and blood pressure control
Amount £1,235,472 (GBP)
Funding ID G1002082 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2012 
End 12/2016
 
Title PMCA1 cardiac specific knock-out 
Description The mice carry a genetic deletion for the isoform 1 of the plasma membrane calcium pump specifically in the cardiac muscle cells. This mouse model is used to understand the molecular mechanisms underlying the development and progression of cardiac hypertrophy and heart failure. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact ongoing 
 
Title PMCA1 floxed mice 
Description The mice carry a small genetic mutation (loxP) flanking a critical component of the PMCA1 gene. Upon crossing with a mouse line expressing Cre recombinase under a gene-specific promoter the genetic deletion for the isoform 1 of the plasma membrane calcium pump will occur in specific tissues or point in time. This mouse model is used to understand the role of PMCA1 in health and disease. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2013 
Provided To Others? Yes  
Impact This model is valuable for any researcher wishing to investigate the role of PMCA1 in health and disease. The impact of this model are ongoing. It was given to a reserch group in USA 
 
Title PMCA1 global heterozygous mouse model 
Description PMCA1 global heterozygous mouse model - model of age dependent essential hypertension 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2017 
Provided To Others? Yes  
Impact Publication: Little, R., Zi, M., Hammad, S.K., Nguyen, L., Njegic, A., Kurusamy, S., Prehar, S., Armesilla, A.L., Neyses, L., Austin, C., Cartwright, E.J. (2017). Reduced expression of PMCA1 is associated with increased blood pressure with age which is preceded by remodelling of resistance arteries. Aging Cell 16, 1104-1113. 
 
Description PMCA1 and development 
Organisation National Institute of Environmental Health Sciences
Country United States 
Sector Academic/University 
PI Contribution Provision of PMCA1 floxed mice
Collaborator Contribution Investigation of the role of PMCA1 in development
Impact -
Start Year 2014
 
Description PMCA1 and intestin 
Organisation Mayo Clinic
Country United States 
Sector Charity/Non Profit 
PI Contribution PMCA1 floxed mice to be used as part of project for which grant funding has been requested. Analysis of some data which was subsequently published.
Collaborator Contribution Research has been published Ryan Z.C., Craig T.A., Filoteo A.G., Westendorf J.J., Cartwright E.J., Neyses L., Strehler E.E., Kumar R. Deletion of the intestinal plasma membrane calcium pump, isoform 1, Atp2b1, in mice is associated with decreased bone mineral density and impaired responsiveness to 1, 25-dihydroxyvitamin D3. Biochemical and Biophysical Research Communications. 2015
Impact Ryan Z.C., Craig T.A., Filoteo A.G., Westendorf J.J., Cartwright E.J., Neyses L., Strehler E.E., Kumar R. Deletion of the intestinal plasma membrane calcium pump, isoform 1, Atp2b1, in mice is associated with decreased bone mineral density and impaired responsiveness to 1, 25-dihydroxyvitamin D3. Biochemical and Biophysical Research Communications. 2015
Start Year 2013
 
Description A novel role for PMCA1 in cardiomyopathy and blood pressure control, Qeen Mary University, London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact attended by medical faculty, post-graduate and undergraduate students

recognition to the group and the University of Manchester
Year(s) Of Engagement Activity 2012
 
Description AHA Basic Cardiovascular Sciences meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact recognition for the University

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Year(s) Of Engagement Activity 2014
 
Description AHA Congress, Orlando 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Health professionals
Results and Impact .....

recognition for the group and the University of Manchester
Year(s) Of Engagement Activity 2011
 
Description HFA Congress Belgrade 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Poster Presentation
Geographic Reach International
Primary Audience Health professionals
Results and Impact ....

recognition for the group and the University of Manchester
Year(s) Of Engagement Activity 2012
 
Description Interview Day at Trininty High School 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Schools
Results and Impact ....
Year(s) Of Engagement Activity 2012
 
Description Invited conference talk (Exeter) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Host of debate at Physiological Society conference - debating the value of using the mouse to understand physiology.
Year(s) Of Engagement Activity 2018
 
Description Invited seminar (Luxembourg) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact University of Luxembourg. Is PMCA1 a heritable risk factor for heart failure? Dr Elizabeth J Cartwright
Year(s) Of Engagement Activity 2018
 
Description Invited seminar (Newcastle) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact University of Newcastle, Institute of Genetic Medicine. Understanding the role of the calcium extrusion pump PMCA in heart failure. Dr Elizabeth J Cartwright
Year(s) Of Engagement Activity 2017
 
Description Invited seminar (Nottingham) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Seminar: University of Nottingham, Faculty of Medicine and Health Sciences. Understanding the role of the calcium extrusion pump PMCA in heart failure. Dr Elizabeth J Cartwright
Year(s) Of Engagement Activity 2018
 
Description School Visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach Local
Primary Audience Schools
Results and Impact Year 12/13 pupils attended the talk enitled "The cardiovascular system in health and disease"

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Year(s) Of Engagement Activity 2013
 
Description The Body Experience 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact General public attended the workshop as part of The Body Experience at Manchester Museum entitled "Go with the bloodflow"

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Year(s) Of Engagement Activity 2013
 
Description Work experience placements 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Schools
Results and Impact ....
Year(s) Of Engagement Activity 2012
 
Description World Heart Day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact ....

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Year(s) Of Engagement Activity 2012