Dissecting the mechanism of action of the renin angiotensin hormone angiotensin1-9

The body produces specific hormones which travel via the bloodstream and engage with receptors which contribute to the normal function of blood vessels, the heart and kidney. The main hormone from this system, angiotensin II, can become overactive and contribute to the development of cardiovascular disease, resulting in high blood pressure (hypertension) and finally enlargement of the heart and damage to kidneys. Although this has been known for a long time (in fact inhibitors of various facets of angiotensin II function are the target for a common group of drugs used to lower blood pressure in patients and treat conditions such as heart failure) the central mechanisms for the functioning of this hormone system are not completely understood. The hormone system has many different roles in the body depending upon the organ on which it acts. Also, new members of this hormone family are being discovered. Here we describe a role for a new hormone in this system, angiotensin 1-9. Angiotensin 1-9 was previously thought to be inactive but we have evidence to support it being an active hormone which inhibits angiotensin II actions. Thus angiotensin 1-9 may be an important therapeutic target in cardiovascular disease. We wish to full understand how this hormone functions and will achieve this using a range of techniques.

The renin angiotensin system (RAS) plays a key role in the development of cardiovascular diseases, including hypertension, cardiac hypertrophy and atherosclerosis. Although cell signalling via the peptide hormone angiotensin (Ang) II is well documented, other peptide hormones, particularly Ang1-7, for example, are also important in the pleiotrophic effects of the RAS in vivo and may antagonise AngII signalling. We have made a novel observation, outlined in supporting data, that the angiotensin metabolite Ang1-9, previously thought to be inactive, is actually an active RAS hormone in its own right. Ang1-9 engages the angiotensin type 2 receptor and is able to inhibit pro-hypertrophic signalling of AngII and other agonists on cardiomyocytes. In this proposal we will fully investigate and dissect the cell signalling mechanisms and in vivo functioning of Ang1-9 with regard to its effects on the heart and cardiomyocytes.