Investigation of the counter-regulatory renin angiotensin system in cardiovascular disease

In the body hormones travel via the bloodstream and engage receptors which contribute to the normal function of blood vessels, heart and kidney. One hormone, angiotensin II, can become overactive and contribute to cardiovascular disease, resulting in high blood pressure, enlargement of the heart and damage to kidneys. However, other members of this hormone family including angiotensin-(1-7) and angiotensin-(1-9) block the detrimental actions of angiotensin II, through mechanisms that are not well understood. Thus angiotensin-(1-7) and –(1-9) may be important therapeutic targets in cardiovascular disease and therefore it is important to fully understand how they function. We investigate the function of these potentially therapeutic peptides using a range of techniques. One of these is the use of gene transfer using viral vectors to express these molecules in different cells to study their function with the ultimate aim of developing new gene therapies. To achieve this we use different viral vectors which are able to efficiently deliver genes into different cell types in organs in the body.

The renin angiotensin system (RAS) is a coordinated hormonal cascade mediating cardiovascular, renal and adrenal function, with pleiotrophic actions including stimulation of oxidative stress, inflammation and growth. The RAS is key to the development of cardiovascular diseases, including hypertension, cardiac remodelling and atherosclerosis and pharmacological RAS antagonists are some of the most successful therapies in hypertension and heart failure. Our understanding of the function of the RAS in individual tissues in vivo is incomplete and discoveries, including the angiotensin converting enzyme (ACE) homologue ACE2 and angiotensin 1-7 [Ang-(1-7)] have highlighted additional key mediators of the RAS which may be therapeutic targets in cardiovascular disease. As well as mediating effects systemically, local tissue-specific generation in organs, including heart, are critical in RAS-mediated effects. Angiotensin II (AngII) is the key regulator, however alternative peptide hormones such as Ang-(1-7) are able to antagonise AngII signalling via engaging a specific receptor, called Mas. We have also recently discovered that Ang-(1-9), a metabolite of the AngII precursor angiotensin I, is a RAS hormone. Previously thought to be an inactive substrate for Ang-(1-7) generation we have demonstrated that Ang-(1-9) is able to antagonise the pathophysiological effects of AngII in cardiomyocytes via the angiotensin type 2 receptor and produces anti fibriotic effects in a model of essential hypertension, the stroke prone spontaneously hypertensive rat (SHRSP). We are now extending these investigations into the effects of Ang-(1-9) and Ang-(1-7) in an angiotensin II-infusion model of hypertension in mice and in vasculare remodelling in acute vascular injury. Furthermore, we are exploring opportunities for the peptides as therapeutics in a mouse model of myocardial infarction and in hypertensive cardiac remodelling using gene therapy approaches via efficient and specific viral vector -mediated gene transfer and direct peptide infusion. We are also investigating the underlying cell signalling mechanisms for each peptide at the protein, gene and microRNA level. Ultimately, we aim to identify therapeutic applications which can be developed in cardiovascular disease.

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Publications

1. Clarke C, Flores-Munoz M, McKinney CA, Milligan G, Nicklin SA. Regulation of cardiovascular remodelling by the by the counter-regulatory axis of the renin angiotensin system. Future Cardiology 2013;9:23-38
2. Flores-Muñoz M, Godinho B, Aziz A, Nicklin SA. Adenoviral gene transfer of angiotensin-(1-7) or angiotensin-(1-9) inhibits cardiomyocyte hypertrophy via the mas receptor or angiotensin type 2 receptor respectively. PLoS ONE 2012;7:e45564
3. Flores-Muñoz M, Work LM, Douglas K, Denby L, Dominiczak AF, Graham D, Nicklin SA. Angiotensin-(1-9) attenuates cardiac fibrosis in the SHRSP via the angiotensin type 2 receptor. Hypertension 2012;59:300-307.
4. Flores-Muñoz M, Smith NJ, Haggerty C, Milligan G, Nicklin SA. Angiotensin1-9 antagonises pro-hypertrophic signalling in cardiomyocytes via the angiotensin type 2 receptor.  J Physiol 2011;589(4):939-51.
5. Masson R, Nicklin SA, Craig M-A, McBride M, Gilday K, Gregorevic P, Allen JM, Chamberlain JS, Smith G, Giordano A, Graham D, Dominiczak AF, Napoli C, Baker AH. Onset of experimental severe cardiac fibrosis is mediated by overexpression of ACE2. Hypertension 2009;53(4):694-700.
6. Waddington SN, McVey JH, Bhella D, Parker AL, Barker K, Atoda H, Pink R, Buckley SMK, Greig JA, Denby L, Custers J, Morita T, Fracishetti IMB, Monteiro RQ, Barouch DH, van Rooijen N, Napoli C, Havanga M, Nicklin SA, Baker AH. Adenovirus serotype 5 hexon mediates liver gene transfer. Cell 2008;132 (3):397-409.
7. Nicklin SA*, White SJ*, Nicol  CG, Von Seggern DJ, Baker AH. In vitro and in vivo characterisation of endothelial cell-selective adenoviral vectors. J Gene Med 2004;6(3):300-308. *Author’s contributed equally.
8. White SJ*, Nicklin SA*, Buening H, Brosnan MJ, Leike K, Papadakis ED, Hallek M, Baker AH. Targeted gene delivery to vascular tissue in vivo by tropism-modified adeno-associated virus vectors. Circulation 2004;109(4):513-519. *Author’s contributed equally.