Role of defective Kv7.4 channels in vascular disease.
Lead Research Organisation:
St George's, University of London
Department Name: Basic Medical Sciences
Abstract
Context: Having high blood pressure increases the chances of heart attacks, strokes or kidney damage and the poor health that is associated with these diseases. Persistently narrowed blood vessels limits the flow of blood to important organs like the kidney, heart or brain and at the same time puts a strain on the heart. Potassium channels produced by the KCNQ family of genes are proteins that provide a pathway to allow potassium ions out of the cell and in doing so reduce the likelihood of muscle cells in the wall of blood vessels from contracting. This in turn improves the ease at which blood flows through blood vessels. Recently the applicant's group showed that these channels contribute to physiological dilators of blood vessels such as adrenaline but they become less effective in high blood pressure.
Aims:The proposed work will study proteins encoded by KCNQ genes in the arteries serving the kidney and brain in rats that have normal blood pressure and ones with high blood pressure. It will also do the same comparison in abdominal arteries from patients undergoing routine surgery who have normal or high blood pressure. The project will identify how these specific protein pores are opened by chemicals found in our blood to keep blood vessels open and to understand how they may become less effective in disease.
Benefits: Understanding how a blood vessel can be kept open is crucial for developing new treatments for when these processes go wrong. The proposed body of work will provide fundamental information on how KCNQ proteins stop blood vessels from becoming overly constricted and the factors that cause these proteins to have less functional impact in disease conditions. As such it will provide new lines of therapeutic treatment as well as enhancing our basic understanding of blood vessel control and disease mechanisms .
Aims:The proposed work will study proteins encoded by KCNQ genes in the arteries serving the kidney and brain in rats that have normal blood pressure and ones with high blood pressure. It will also do the same comparison in abdominal arteries from patients undergoing routine surgery who have normal or high blood pressure. The project will identify how these specific protein pores are opened by chemicals found in our blood to keep blood vessels open and to understand how they may become less effective in disease.
Benefits: Understanding how a blood vessel can be kept open is crucial for developing new treatments for when these processes go wrong. The proposed body of work will provide fundamental information on how KCNQ proteins stop blood vessels from becoming overly constricted and the factors that cause these proteins to have less functional impact in disease conditions. As such it will provide new lines of therapeutic treatment as well as enhancing our basic understanding of blood vessel control and disease mechanisms .
Technical Summary
Opening of voltage-dependent potassium channels encoded by the KCNQ4 gene (Kv7.4) maintain vascular smooth muscle in a relaxed state and also underlie vasodilations by physiological mediators. However, dysfunction of Kv7.4 is a major feature of arteries from hypertensive animals. More importantly, as Kv7.4 has a key role in renal arteries then defective Kv7 channels may be central to the development of high blood pressure. The intended project will build upon the foundation studies by the applicant and will determine by quantitative PCR and western blot analysis how the expression of KCNQ genes alters in the renal and cerebral arteries as rats develop hypertension. KCNE1-5 gene products alter the biophysical properties of Kv7.4 so this project will use a molecular interference approach to assess the role of KCNE-products in vascular tone and will determine how the expression of these genes is affected by hypertension. These studies will be consolidated by isometric tension recording and patch clamp electrophysiology on isolated smooth muscle cells and HEK293 cells heterologously expressing KCNQ4, which will define how the Kv7.4 channel is stimulated by beta-adrenoceptor agonists. The factors dictating the membrane abundance of Kv7.4 and the impact of angiotensin II on protein levels will be elucidated by Western blot analysis and immunocytochemistry.
Planned Impact
The goal of the research is that through a better understanding of how Kv7 channels govern vascular tone novel therapeutics for vascular disease can be developed. These findings can also be applied to other non-vascular smooth muscle (eg uterus) where Kv7 channels have been shown to have a functional role. There are a number of beneficiaries to this research beyond researchers in the immediate and allied fields.
1. Phd students and undergraduates at St George's as well as research staff from collaborators labs will benefit from the findings of the proposed research and the energetic environment it generates. Undergraduates on the medical and biomedical science degrees will benefit as the applicant includes his research in lectures on current views on vascular biology. This has the added benefit that these undergraduates are the future end users of the research.
2. Clinicians within the SouthWest London Academic Network will benefit from an increased awareness of vascular physiology and possible novel therapeutics through the Annual St George's Research Day organised by the applicant.
3. Healthcare professionals in general will benefit from this research because of the increased understanding of vascular physiology and the mechanisms of disease. They will appreciate that advancing Biomedical science leads to new treatment rationales. Findings will be disseminated to these beneficiaries through targeted press releases from the St George's media office, through attendance at Clinical meetings such as the British Hypertension Society and through collaborators Institutional-hospital communications (eg University of Copenhagen Faculty of Medical Sciences, St Thomas' London).
4. There is much interest by the Pharmaceutical Industry in Kv7 activators with the development of retigabine as a first in class anti-convulsant highlighted by the Industrial symposium on Kv7 channels held in Copenhagen in 2010, at which the applicant spoke. A number of companies have shown interest in the applicant's work because the existence of these channels in smooth muscle underlies a number of the side effects of agents such as retigabine. Pharmaceutical Companies will benefit from the findings of the research because side effects of compounds designed for neuronal disorders can be minimized through developing agents that have a greater Kv7 isoform selectivity. Moreover, new therapeutics can be developed using the same rationale but targeting the smooth muscle isoforms.
5. Charities such as the British Heart Foundation or Kidney Research UK will benefit from a better awareness of what research activity is advancing understanding of disease states. It is important that charities that support Biomedical research in the UK and gliobally appreciate that basic science does not generate a cure overnight but enhanced understanding of physiology and pathophysiology informs future healthcare procedures, pharmacological and non-pharmacological.
1. Phd students and undergraduates at St George's as well as research staff from collaborators labs will benefit from the findings of the proposed research and the energetic environment it generates. Undergraduates on the medical and biomedical science degrees will benefit as the applicant includes his research in lectures on current views on vascular biology. This has the added benefit that these undergraduates are the future end users of the research.
2. Clinicians within the SouthWest London Academic Network will benefit from an increased awareness of vascular physiology and possible novel therapeutics through the Annual St George's Research Day organised by the applicant.
3. Healthcare professionals in general will benefit from this research because of the increased understanding of vascular physiology and the mechanisms of disease. They will appreciate that advancing Biomedical science leads to new treatment rationales. Findings will be disseminated to these beneficiaries through targeted press releases from the St George's media office, through attendance at Clinical meetings such as the British Hypertension Society and through collaborators Institutional-hospital communications (eg University of Copenhagen Faculty of Medical Sciences, St Thomas' London).
4. There is much interest by the Pharmaceutical Industry in Kv7 activators with the development of retigabine as a first in class anti-convulsant highlighted by the Industrial symposium on Kv7 channels held in Copenhagen in 2010, at which the applicant spoke. A number of companies have shown interest in the applicant's work because the existence of these channels in smooth muscle underlies a number of the side effects of agents such as retigabine. Pharmaceutical Companies will benefit from the findings of the research because side effects of compounds designed for neuronal disorders can be minimized through developing agents that have a greater Kv7 isoform selectivity. Moreover, new therapeutics can be developed using the same rationale but targeting the smooth muscle isoforms.
5. Charities such as the British Heart Foundation or Kidney Research UK will benefit from a better awareness of what research activity is advancing understanding of disease states. It is important that charities that support Biomedical research in the UK and gliobally appreciate that basic science does not generate a cure overnight but enhanced understanding of physiology and pathophysiology informs future healthcare procedures, pharmacological and non-pharmacological.
Publications
Askew Page HR
(2019)
TMEM16A is implicated in the regulation of coronary flow and is altered in hypertension.
in British journal of pharmacology
Barrese V
(2018)
KCNQ-Encoded Potassium Channels as Therapeutic Targets.
in Annual review of pharmacology and toxicology
Barrese V
(2020)
SMIT (Sodium-Myo-Inositol Transporter) 1 Regulates Arterial Contractility Through the Modulation of Vascular Kv7 Channels.
in Arteriosclerosis, thrombosis, and vascular biology
Barrese V
(2017)
Proliferative Role of Kv11 Channels in Murine Arteries.
in Frontiers in physiology
Barrese V
(2015)
Protective role of Kv7 channels in oxygen and glucose deprivation-induced damage in rat caudate brain slices.
in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
Barrese V
(2018)
Angiotensin II Promotes KV7.4 Channels Degradation Through Reduced Interaction With HSP90 (Heat Shock Protein 90).
in Hypertension (Dallas, Tex. : 1979)
Carr G
(2016)
MicroRNA-153 targeting of KCNQ4 contributes to vascular dysfunction in hypertension.
in Cardiovascular research
Chadha P
(2014)
Contribution of Kv7.4/Kv7.5 Heteromers to Intrinsic and Calcitonin Gene-Related Peptide-Induced Cerebral Reactivity
in Arteriosclerosis, Thrombosis, and Vascular Biology
Corbin A
(2015)
Development of a Model for Excitability Studies using Xenopus Oocytes
in Biophysical Journal
Greenwood I
(2020)
Trying to keep calm in troubled times: The role of K channels in uterine physiology
in Current Opinion in Physiology
Jepps TA
(2016)
Molecular and functional characterization of Kv 7 channels in penile arteries and corpus cavernosum of healthy and metabolic syndrome rats.
in British journal of pharmacology
Jepps TA
(2015)
Fundamental role for the KCNE4 ancillary subunit in Kv7.4 regulation of arterial tone.
in The Journal of physiology
Jepps TA
(2014)
Vasorelaxant effects of novel Kv 7.4 channel enhancers ML213 and NS15370.
in British journal of pharmacology
Molbaek K
(2015)
Localization of the P. Falciparum K+ Channels (PFKCH1 and 2) and Functional Expression in Yeast
in Biophysical Journal
Mondéjar-Parreño G
(2020)
Uncovered Contribution of Kv7 Channels to Pulmonary Vascular Tone in Pulmonary Arterial Hypertension.
in Hypertension (Dallas, Tex. : 1979)
Povstyan O
(2015)
Gß? Subunits Modulation of Kv7.4 Channels Expressed in HEK293 Cells at the Single Channel Level
in Biophysical Journal
Povstyan OV
(2017)
Synergistic interplay of Gß? and phosphatidylinositol 4,5-bisphosphate dictates Kv7.4 channel activity.
in Pflugers Archiv : European journal of physiology
Stott JB
(2015)
G-protein ß? subunits are positive regulators of Kv7.4 and native vascular Kv7 channel activity.
in Proceedings of the National Academy of Sciences of the United States of America
Stott JB
(2016)
Kv7 Channel Activation Underpins EPAC-Dependent Relaxations of Rat Arteries.
in Arteriosclerosis, thrombosis, and vascular biology
Stott JB
(2014)
K(V)7 potassium channels: a new therapeutic target in smooth muscle disorders.
in Drug discovery today
Stott JB
(2018)
Investigating the Role of G Protein ß? in Kv7-Dependent Relaxations of the Rat Vasculature.
in Arteriosclerosis, thrombosis, and vascular biology
Stott JB
(2015)
Contribution of Kv7 channels to natriuretic peptide mediated vasodilation in normal and hypertensive rats.
in Hypertension (Dallas, Tex. : 1979)
Testai L
(2016)
Expression and function of Kv7.4 channels in rat cardiac mitochondria: possible targets for cardioprotection.
in Cardiovascular research
Van Der Horst J
(2020)
Cyclic AMP-Dependent Regulation of Kv7 Voltage-Gated Potassium Channels.
in Frontiers in physiology
Description | Head of Vascular Research Group at the University of Copenhagen |
Organisation | University of Copenhagen |
Country | Denmark |
Sector | Academic/University |
PI Contribution | I travel to Copenheagen every 6-7 weeks for approximately 3 days to organise research meetings and initiate funding strategies. A symposium on Vascular Biology was organised and held in March 2014. Moreover, I organised a session at the Scandinavain Physiological Society meeting in Stockholm, August 2014. A post-doc funded by this initiative has now won a Marie-Curie H2020 Fellowship. |
Collaborator Contribution | The head of the Ion Channel group in Copenhagen has contributed to 50 % of a PhD studentship |
Impact | Two research papers published, one under review and one under construction. One new grant from Novo Nordsk Foundation to fund a Danish post-doc and one Marie-Curie Fellowship |
Start Year | 2013 |
Description | Karl Sward Lund |
Organisation | Lund University |
Country | Sweden |
Sector | Academic/University |
PI Contribution | We were contacted by Prof Sward after our work on microRNA regulation of Potassium channels was published. His group are experts in microRNAs and he saw a numbe rof parallels on transcriptional regualtion |
Collaborator Contribution | Lund have large transcriptional databases from a number of human samples and disease models. |
Impact | None yet |
Start Year | 2016 |
Description | BHF comedy night fundraiser |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | I was the soul organiser of a night of comedy in aid of the BHF. Recruited 6 comedians, arranged the stage and seating, created all publicity and sold all tickets. |
Year(s) Of Engagement Activity | 2018,2020 |
Description | BHF workshop |
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 | Spoke to coronary care patients and carers at the Annual Meeting of the British Cardiovascular society in Glasgow. |
Year(s) Of Engagement Activity | 2018 |
Description | Organised the 1st International Kv7 channels conference in NAples 2019 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Organised the first gathering of any researcher interested in Kv7 channels from University and Industry |
Year(s) Of Engagement Activity | 2019 |
Description | Re-branding of the British Pharmacological Society |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Participants in your research and patient groups |
Results and Impact | The British Pharmacological Society has an International membership and reach. However, its branding does not equate to its International perception. The first task since become VP for External Affairs was to hire a branding agency to undergo research and then deliver a new brand concept based upon that research. The research of the consultation are unknown but will ultimately lead to a whole re-branding of a learned society |
Year(s) Of Engagement Activity | 2014 |
Description | Scandinavian Physiological Society |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Created a cross Scandinavian Vascular Biology Symposium located in Copenhagen, which was adopted by the Scandinavian Physiological Society leading to the creation of a vascular special interest group. |
Year(s) Of Engagement Activity | 2014,2016 |