Mechanosensitive regulation of cardiac excitation-contraction coupling: The role of localized beta-adrenergic receptors and calcium channels
Lead Research Organisation:
Imperial College London
Department Name: National Heart and Lung Institute
Abstract
When a heart fails to function properly it may be possible to reduce its workload and assist its role in providing blood to the different organs in the body by the use of mechanical pumps, known as left ventricular assist devices. The devices induce profound changes in the heart leading, in some cases, to significant improvements in heart function. It is thought that one of the elements that respond promptly to this treatment is the cardiac cell. In this project we aim to investigate how this cell changes in response to treatment with left ventricular assist devices. We will study isolated cells from the hearts of rats that are exposed to a reduction in mechanical load, in a similar fashion to hearts treated with left ventricular assist devices. Using sophisticated microscopic techniques we will study the response of molecules that are involved in the function of the cells and determine if they are responsible for changes in function. This research will help understanding the mechanisms responsible for poor function of the heart and provide potential targets for the treatment of patients.
Technical Summary
There is emerging interest in the potential of mechanical unloading of failing hearts using Left Ventricular Assist Device (LVAD) therapy to improve myocardial function. Recently it has been shown that LVAD support restores beta-adrenergic responsiveness and reverses receptor downregulation in failing human hearts. In this project we aim to study cAMP -beta receptors signalling in cardiomyocytes (CMs) isolated from rat hearts after mechanical unloading using a novel SICM/FRET technique. Mechanical unloading for periods of different duration will be induced in normal and failing rat hearts by heterotopic abdominal heart transplantation. The localized dynamics of cAMP-beta-receptors and the compatmentalisation of the signalling will be determined in isolated cardiomyocytes from control and unloaded hearts.
In the second part of the project we will investigate the role of L type Calcium channels in the recovery of unloaded cells. We will look at the distribution of channels and correlate this with restoration of cellular architecture and membrane topography.
This project will provide a mechanistic insight in the relationship between chronic changes in load and functional properties of the myocardium, and provide new information on the molecular and signalling effects of mechanical unloading during myocardial remodelling in heart failure.
In the second part of the project we will investigate the role of L type Calcium channels in the recovery of unloaded cells. We will look at the distribution of channels and correlate this with restoration of cellular architecture and membrane topography.
This project will provide a mechanistic insight in the relationship between chronic changes in load and functional properties of the myocardium, and provide new information on the molecular and signalling effects of mechanical unloading during myocardial remodelling in heart failure.
Planned Impact
The proposed study is fundamental in its nature, aiming to understand basic mechanisms of cardiac myocyte reaction to mechanical unloading. This study will generate new knowledge that would be of immediate interest to researchers in heart failure and in cardiac biology in general. In the longer term this should help define new strategies to ameliorate cellular function in failing hearts. This work will be of interest to researchers in translational medicine and finally will result in more specific health care and therapeutic approaches. This would be highly beneficial to human health and wealth both within and outside the UK.
Besides publication in specialized scientific journals we anticipate that the results of this work will be widely publicised as they have substantial value for the general public.
Dr Julia Gorelik's recent work, first published in "Science " magazine, has been covered extensively on many news websites including the Pharma Times, US Clinical Researcher, Medical Device Guru, Cordis News and Science Daily. It is also covered on the Wellcome Trust's website and in the 15th of March edition of 360, the newspaper of Imperial College Healthcare NHS Trust. Links to some examples of the coverage are below.
Examples of coverage:
Bear chemical brings heart hope - BBC News Health;
Bear chemical could help to prevent arrhythmia in heart attack sufferers- The Daily Mail;
Synthesized Compound Also Found in Bear Bile Chemical Could Help Keep Hearts in Rhythm - Science Daily;
New microscopy technique could mean more effective beta-blockers - PharmaTimes
Nanotech scanning used to assess heart damage - British Standards Institution
New microscopy technique could mean more effective beta-blockers - US Clinical Researcher
Detailed insight into failing heart cells gained using new nano ... - Science Daily
Researchers gain detailed insight into failing heart cells using ... - PhysOrg
Nano-imaging technique gives clues to failing hearts | Wellcome Trust - Wellcome Trust
Nanoscale heart imaging - Medical Device Guru
Besides publication in specialized scientific journals we anticipate that the results of this work will be widely publicised as they have substantial value for the general public.
Dr Julia Gorelik's recent work, first published in "Science " magazine, has been covered extensively on many news websites including the Pharma Times, US Clinical Researcher, Medical Device Guru, Cordis News and Science Daily. It is also covered on the Wellcome Trust's website and in the 15th of March edition of 360, the newspaper of Imperial College Healthcare NHS Trust. Links to some examples of the coverage are below.
Examples of coverage:
Bear chemical brings heart hope - BBC News Health;
Bear chemical could help to prevent arrhythmia in heart attack sufferers- The Daily Mail;
Synthesized Compound Also Found in Bear Bile Chemical Could Help Keep Hearts in Rhythm - Science Daily;
New microscopy technique could mean more effective beta-blockers - PharmaTimes
Nanotech scanning used to assess heart damage - British Standards Institution
New microscopy technique could mean more effective beta-blockers - US Clinical Researcher
Detailed insight into failing heart cells gained using new nano ... - Science Daily
Researchers gain detailed insight into failing heart cells using ... - PhysOrg
Nano-imaging technique gives clues to failing hearts | Wellcome Trust - Wellcome Trust
Nanoscale heart imaging - Medical Device Guru
Organisations
Publications
Bastug-Özel Z
(2019)
Heart failure leads to altered ß2-adrenoceptor/cyclic adenosine monophosphate dynamics in the sarcolemmal phospholemman/Na,K ATPase microdomain
in Cardiovascular Research
Judina A
(2020)
Studying signal compartmentation in adult cardiomyocytes.
in Biochemical Society transactions
Perbellini F
(2018)
Investigation of cardiac fibroblasts using myocardial slices.
in Cardiovascular research
Peter T Wright
(2017)
Abstract
Sanchez-Alonso J
(2018)
Function of L-Type Calcium Channel Microdomain in Human Myocytes from Hearts with Ischemic versus Dilated Cardiomyopathies
in Biophysical Journal
Sanchez-Alonso JL
(2016)
Microdomain-Specific Modulation of L-Type Calcium Channels Leads to Triggered Ventricular Arrhythmia in Heart Failure.
in Circulation research
Schultz F
(2019)
Cardiomyocyte-myofibroblast contact dynamism is modulated by connexin-43.
in FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Surdo NC
(2017)
FRET biosensor uncovers cAMP nano-domains at ß-adrenergic targets that dictate precise tuning of cardiac contractility.
in Nature communications
Swiatlowska P
(2020)
Microtubules regulate cardiomyocyte transversal Young's modulus.
in Proceedings of the National Academy of Sciences of the United States of America
Title | Models of cardiomyocytes |
Description | 3D models of the cardiomyocytes and cell-cell interactions with functional microdomains including receptors and ion channels |
Type Of Art | Artistic/Creative Exhibition |
Year Produced | 2015 |
Impact | The cellular model was presented on Green Man festival. Show to general people the cardiomyocyte structure. |
Title | The Heart and Lung Convenience store |
Description | interactive exhibits, activities and installations about heart and lung |
Type Of Art | Artistic/Creative Exhibition |
Year Produced | 2015 |
Impact | show the scientific activity for general public |
Title | The Heart and Lung Repair Shop |
Description | interactive exhibits, activities and installations about heart and lung |
Type Of Art | Artistic/Creative Exhibition |
Year Produced | 2014 |
Impact | A lot of intrest from schoolchildren and public |
Title | CytoCypher application, programme and calculation for cardiomyocytes |
Description | High-Throughput Method for contraction and calcium dynamics |
Type Of Material | Technology assay or reagent |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | This programme people can use for their cardiovascular research |
Description | Collaboration with Rock and Jazz Society at Imperial Festival |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | interactive experiment looking at the effect of music upon the cardiovascular system using electrocardiography Intrest from schoolchildren |
Year(s) Of Engagement Activity | 2014 |
Description | Heart and Lung Convenience store |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | To show the general public the scientific activity in cardiovascular research |
Year(s) Of Engagement Activity | 2015 |
Description | Imperial College Festival |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Stem Cell Exhibit Intrest in stem cells |
Year(s) Of Engagement Activity | 2012 |
Description | Imperial College Festival |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Stem Cell Exhibit, discussion about stem cells during exhibition Intrest from school children about stem cell research |
Year(s) Of Engagement Activity | 2013,2014 |
Description | Imperial Fringe Festival |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | 'Scared to Death' Stall on which my PhD student gave talks and presented exhibits on the theme of 'The science of our fears'! Intrest in science |
Year(s) Of Engagement Activity | 2012,2013,2014 |
Description | MasterCard Priceless London Event |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | Performed in the Punk Science show at the science museum. Gave a talk regarding work with stress cardiomyopathy ( discussion after talk) Intrest from schoolchildren |
Year(s) Of Engagement Activity | 2013 |
Description | NHLI Heart and Lung Repair Shop-Pub Quiz |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Assisted in the running of a Pub Quiz as part of the NHLI's Heart and Lung Repair Shop 'pop-up' installation |
Year(s) Of Engagement Activity | 2015 |
Description | Punk Science |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Punk Science is the museums in house comedy duo and they perform a science comedy show at the IMAX theatre during various events. Provided the concept and helped them produce material in their show |
Year(s) Of Engagement Activity | 2013,2014 |
Description | Science Communication |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Involved with public relations campaigns to protect bioscience from attacks, either in the media or physically, by anti-vivisectionist organizations. This has comprised of written pieces for Imperial Reporter and 'Speaking of Research'. It has also involved petitioning the government and lobbying industry to gain support for academic scientists. |
Year(s) Of Engagement Activity | 2012,2014,2015 |
Description | Science Museum show |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | Performed in the Punk Science show in IMAX Theatre. Show concerned aspects of regenerative medicine in cardiac research( discussion after talk) Intrest from schoolchildren |
Year(s) Of Engagement Activity | 2014 |
Description | Speaking of Research |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Authored piece on modular training requirements for home office licences to work with animals . ( discussion about animal work) Discussion about importance of animal work |
Year(s) Of Engagement Activity | 2013 |
Description | Wohl Reachout Lab |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | Conducted 4+ day long seminars with disadvantaged school pupils (Westminster Academy age 14-18) at Imperial College's Wohl reach-out laboratories. These involve a day-long practical concerning anatomy, physiology or molecular biology. |
Year(s) Of Engagement Activity | 2014,2015 |