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Assessing therapeutic strategies to target the counter-regulatory renin-angiotensin system in cardiovascular disease


   Institute of Cardiovascular and Medical Sciences

  Prof Stuart Nicklin, Dr Chris Loughrey, Dr Lorraine Work  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Project outline: 

The renin angiotensin system (RAS) is a hormonal cascade mediating cardiovascular function. The RAS is key to the development of cardiovascular diseases, including cardiac remodelling in hypertension and heart failure and atherosclerosis. A counter-regulatory RAS exists, centred on the angiotensin converting enzyme (ACE) homologue ACE2 and angiotensin 1-7 [Ang-(1-7)], highlighting additional key mediators of the RAS which may be therapeutic targets in cardiovascular disease.

We have also discovered that Ang-(1-9), a metabolite of the Angiotensin II precursor angiotensin I, is a RAS hormone. We have demonstrated that Ang-(1-9) is able to antagonise the pathophysiological effects of AngII in cardiomyocytes, fibroblasts and vascular smooth muscle cells via the angiotensin type 2 receptor.

We are now investigating therapeutic approaches for peptides and enzymes of the counter-regulatory axis of the renin angiotensin system using adenoviral and adeno-associated viral gene transfer vectors and extracellular vesicles as delivery vehicles in cardiovascular disease models including hypertensive cardiomyopathy, myocardial infarction and acute vascular injury.

Project aims: 

To develop and assess molecular therapeutic approaches to deliver counter-regulatory renin angiotensin system components in cardiovascular disease.

Techniques used: 

Cell culture in both primary cells and cell lines and in vivo models of cardiovascular disease, molecular biology techniques, construction and testing of replication deficient viral gene transfer vectors, isolation and characterisation of extracellular vesicles.

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References

C Fattah, K Nather, CS McCarroll, M Hortigon, V Zamora Rodriguez, M Flores-Munoz, L McArthur, L Zentilin, M Giacca, RM Touyz, GL Smith, C Loughrey, SA Nicklin. Gene therapy with angiotensin-(1-9) preserves left ventricular systolic function post-myocardial infarction via a direct inotropic effect. (2016). THE JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 68: 2652-2666.
C McKinney, C Fattah, C Loughrey, SA Nicklin. (2014). Cardiac and vascular remodelling: effects of the counter-regulatory renin angiotensin system peptides, Ang-(1-7) and Ang-(1-9). CLINICAL SCIENCE, 126: 815-827.
M Flores-Muñoz, LM Work, K Douglas, L Denby, AF Dominiczak, D Graham, SA Nicklin. (2012). Angiotensin-(1-9) attenuates cardiac fibrosis in the SHRSP via the angiotensin type 2 receptor. HYPERTENSION, 59(2):300-307.
A Pashova, LM Work and SA Nicklin. (2020). The role of extracellular vesicles in neointima formation post vascular injury. CELLULAR SIGNALLING, 18;76:109783. doi: 10.1016/j.cellsig.2020.109783.
McFall A, Nicklin SA, Work LM. The counter regulatory axis of the renin angiotensin system in ischaemic stroke: insight from preclinical studies and potential as a therapeutic target. CELLULAR SIGNALLING, 2020 Dec;76:109809. doi: 10.1016/j.cellsig.2020.109809. Epub 2020 Oct 13.
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