The Cardiac Role of the Exchange Protein Directly Activated by cAMP (Epac) During Postnatal Development
Lead Research Organisation:
University of Bristol
Department Name: Clinical Science at South Bristol
Abstract
During postnatal development, heart cells undergo marked changes in shape and size in order to adapt to a changing and growing organism. In addition there are changes in the way heart cells generate their electrical and contractile activity. Recent advances in research have identified a new mediator associated with the "flight or fight" conditions where the heart needs to produce more force and beat faster. Little is known about this mechanism during different stages of development and how it changes, as the heart moves towards its adult state. Interestingly, this mechanism has also been linked to protecting the heart against cardiac insults (e.g. hypoxia, a lack of oxygen flowing into the heart, or ischaemia, a stoppage in blood flow). This study aims to identify the changes that occur in the heart during development and when the heart is exposed to cardiac insults. Particular emphasis will be placed on this new mechanism. The information which we aim to gain will help to plan and develop ways to protect the developing heart, and may ultimately help tailor such strategies for use in paediatric open-heart surgery. This is important as interventions that protect the heart that are proven in adult hearts have been uncritically extended to immature hearts without taking into account these important differences as a developing heart changes.
Technical Summary
The vulnerability of the myocardium to cardiac insults changes during postnatal development. The underlying mechanism(s) are not presently known although developmental changes in Ca2+ mobilisation could be responsible. Key regulation of cardiac Ca2+ cycling is mediated via cyclic AMP (cAMP) /protein Kinase A (PKA) signalling pathway. Recent work has also identified guanine nucleotide exchange factor directly activated by cAMP (Epac) as an additional independent and parallel cAMP signalling pathway which also appears to regulate Ca2+ cycling in cardiomyocytes. Little is known about the role of Epac in health and disease with nothing known about the role of Epac during postnatal development. The aim of this project is to test the hypothesis that "postnatal developmental changes in cAMP /Epac signalling pathways alter Ca2+ cycling under normal conditions and during cardiac insults independent of the cAMP/PKA pathway". This work will answer fundamental questions relating to developmental changes in regulation of Ca2+ cycling and will aid the rational development of strategies to protect the developing heart.
Planned Impact
The immediate beneficiaries of this research are the basic and clinical scientists in Bristol working and interested in novel mechanisms to protect the adult and immature heart. Although this work will focus on the role of cAMP/PKA/Epac in the heart, data and information will also have impact on colleagues working on other organs (e.g. brain and kidneys) where this signalling pathway may also have protective effects. The content of the research itself has the potential to lead to development of cardioprotective strategies for use during surgery for congenital heart diseases, although as this work is concentrating on basic fundamental biology, it is likely to be some years before this potential is realised.
In a wider sense, this proposed research will significantly contribute to the development of the applicant as a clinical academic. This supports the ongoing drive for Integrated Academic Training of clinicians, and strengthens academic Anaesthesia within the region and nationally. This will assist in the dissemination of translational research knowledge and skills to other clinicians in the area.
In a wider sense, this proposed research will significantly contribute to the development of the applicant as a clinical academic. This supports the ongoing drive for Integrated Academic Training of clinicians, and strengthens academic Anaesthesia within the region and nationally. This will assist in the dissemination of translational research knowledge and skills to other clinicians in the area.
People |
ORCID iD |
Martin Lewis (Principal Investigator / Fellow) |
Publications
Cardiovascular Sciences I
(2016)
International Academy of Cardiovascular Sciences (IACS) 3rd European Section Meeting, 2016
in Current Research: Cardiology
Horvath C
(2021)
Inhibition of Cardiac RIP3 Mitigates Early Reperfusion Injury and Calcium-Induced Mitochondrial Swelling without Altering Necroptotic Signalling.
in International journal of molecular sciences
Horvath C
(2022)
Relevance of necroptosis in the hearts subjected to acute versus chronic ischemia/reperfusion injury
in Cardiovascular Research
Lewis M
(2018)
Consecutive Isoproterenol and Adenosine Treatment Confers Marked Protection against Reperfusion Injury in Adult but Not in Immature Heart: A Role for Glycogen
in International Journal of Molecular Sciences
Lewis Martin J.
(2019)
Simultaneous activation of PKA and Epac is cardioprotective in neonatal and adult hearts
Lewis MJ
(2022)
Cardioprotection of Immature Heart by Simultaneous Activation of PKA and Epac: A Role for the Mitochondrial Permeability Transition Pore.
in International journal of molecular sciences
Mukhamadiyarov RA
(2018)
Size-Dependent Ability of Liposomes to Accumulate in the Ischemic Myocardium and Protect the Heart.
in Journal of cardiovascular pharmacology
Description | Elected Member of the Council for the International Academy for Cardiovascular Sciences- European section |
Geographic Reach | Europe |
Policy Influence Type | Membership of a guideline committee |
Impact | provide support and guidance to young researchers |
Title | Neonatal rat heart proteome |
Description | I have generated a series of semi- quantitative proteomes for rat heart of 7- to 28- days post natal for comparison with the adult rat heart proteome. This is for baseline total, and phospho- proteins. |
Type Of Material | Database/Collection of data |
Provided To Others? | No |
Impact | Presented at NA IACS 2016 meeting, QC, Canada. Will in future be used for the interpretation of data derived from ex vivo perfusion experiments and isolated cardiomyocyes as part of my doctoral thesis. |
Description | ACTACC Conference, Bristol 2018 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Attendance and presentation at Association of Cardiothoracic Anaesthetists Annual Scientific Meeting. Poster prize awarded |
Year(s) Of Engagement Activity | 2018 |
Description | BHF Funding visit |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Supporters |
Results and Impact | A large proportion of the research in my insitute is funded by the British Heart Foundation. They fund a chair here, and were interested to know what other research takes place in the wider research community and so my work was presented as part of the funding renewal application. |
Year(s) Of Engagement Activity | 2016 |
Description | ESC conference: Frontiers in Cardiovascular Biology 2012 in London |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | A lot of interest in the poster presentation. Feedback on our work helps in future preparations and output. |
Year(s) Of Engagement Activity | 2012 |
Description | Frontiers in Biology ESC |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Type Of Presentation | Poster Presentation |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Interaction with European colleagues Scientific interaction |
Year(s) Of Engagement Activity | 2012 |
Description | IACS-ES 2018; Smolenice, Hungary |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Conference attendance |
Year(s) Of Engagement Activity | 2018 |
Description | International Academy of Cardiovascular Sciences (North American Section) Meeting 2016 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | An oral and poster presentation at Sherbrooke, Quebec, Canada for an international association of cardiovascular scientists and Doctors, entitled "Age related differences in the Cardiac Proteome of proteins involved in Signalling and Response to Ischaemia" |
Year(s) Of Engagement Activity | 2016 |
URL | https://www.fourwav.es/view/280/info/ |
Description | Poster presentation- British Society for Cardiovascular Research Annual Scientific Meeting |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Poster presentation of "CYCLOSPORINE A IS PROTECTIVE AGAINST OXIDATIVE STRESS IN ADULT BUT NOT IN IMMATURE ISOLATED CARDIOMYOCYTES" |
Year(s) Of Engagement Activity | 2017 |
URL | http://www.bscr.org/Meetings/Autumn_2017.html |
Description | Presentation at IACS-ES 2017, Pecs, Hungary |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | A poster presentation of my research at an international conference. |
Year(s) Of Engagement Activity | 2017 |
URL | http://www.iacses.com/ |
Description | School Visit (St. Paul's School, London) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | I was invited to give a presentation of my research and my research group's science to a group of schoolchildren interested in biology and medicine. |
Year(s) Of Engagement Activity | 2017 |
Description | Society of Cardiothoracic Surgeons 2017 Meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | c. 50 attendees at oral presentation at Society of Cardiothoracic Surgeons annual research meeting, for presentatoin entitled "Phosphodiesterase 5A is a potential target for Cardioprotection in Surgery with Neonates for Congenital Heart Disease". |
Year(s) Of Engagement Activity | 2017 |
URL | https://www.myeventflo.com/event-lecture.asp?lectID=11859&list=1 |