Robin Carroll, Emeritus Professor of Haematology from the University of Cambridge.
New insights into protein shape may provide novel treatments for serious diseases of the circulatory system. High blood pressure, also called ‘hypertension’, is a major risk factor for cardiovascular disease in the UK, while ‘pre-eclampsia’ is a potentially life-threatening state of acutely raised blood pressure that affects pregnant women.
Meera - Pre-eclampsia is unfortunately quite common, with 10 women and 1,000 babies dying from it in the UK every year. There are various factors in the mother that contribute to the disease, inducing pre-existing hypertension; heart rate; and also the constriction (narrowing) of blood vessels, which raises blood pressure. Robin Carrell from the University of Cambridge is looking into this latter cause, and he told me more about the proteins that are responsible for blood vessel constriction.
Robin - A major factor is a peptide hormone called angiotensin which directly results in a tightening, or vasoconstriction, of small blood vessels. Angiotensin originates from a large protein that circulates in our blood called angiotensinogen. The hormone is released by an enzyme from the kidney called rennin, and the renin cleaves off the terminal part of this circulating protein angiotensinogen to give this very small peptide hormone, angiotensin.
Meera - You’ve been looking at the actual structure of this angiotensinogen protein to see what happens to it to release angiotensin.
Robin - The first and very satisfying finding is that angiotensinogen is far from being a passive source of the hormone. It interacts in a very active way with the enzyme renin. The cleavage site that renin acts to release angiotensin is buried within the angiotensinogen molecule and we demonstrated this, and were also able to demonstrate the way that the interaction with renin results in the cleavage site becoming accessible, changing from the interior of the molecule to the exterior of the molecule. So we’re now seeing that angiotensinogen plays an active and positive part in what is the initiation of the main process of controlling blood pressure.
Meera - What actually happens to it for it to become exposed?
Robin - The surprise to us and to all was the presence of a ‘hidden’ switch, a fine tuning mechanism that controls the activity of the interaction between renin and angiotensinogen that release the hormone and this switch is based on a disulphide bond; a bond between 2 sulphurs. Now in the case of angiotensinogen, with this disulphide bond they are liable, or susceptible, to being broken as the molecule changes from an oxidising to a reducing environment. In a reducing environment, the bridge between the 2 sulphurs is broken and the two parts of the molecule can move apart. In an oxidising environment, the 2 sulphurs are bonded and held together and they hold the molecule in a more active shape, that is they more readily release the hormone angiotensinogen, that controls blood pressure.
Meera - If the angiotensinogen is in an oxidised environment, does that mean it is therefore more exposed and therefore more likely to be cleaved by the renin and for the hormone to be released?
Robin - That is right, that the molecule exists in two forms and they switch from one to another as the protein moves from a reducing environment to and oxidising environment.
Meera - Why would taking a therapeutic approach using this early mechanism be better than current treatments for hypertension?
Robin - It needs to be emphasised that what we’re looking at is the initiating stage in the release of the hormone angiotensin. There is a second stage where the hormone is refined into the form that actually interacts with the arteries and this second stage is controlled by an enzyme for which there have now been designed a series of inhibitors, people may well know them as the ACE inhibitors, that are used very effectively to treat blood pressure. But the major problem is that ACE inhibitors are contraindicated, for very good reasons, in pregnancy. And it is in pregnancy that we get one of the greatest challenges for hypertension for people in the prime years of their life: pre-eclampsia, which affects 2-7% of all pregnancies. Pre-eclampsia is still not well understood, so what we’ve done is add a facet of understanding because we’ve shown specifically the change of angiotensin to the more active, oxidised form takes place in pre-eclampsia. It opens prospects for what was otherwise has been a very resistant condition. That is, the high blood pressure of pregnancy that is the accompanying and prime feature of pre-eclampsia.
Meera - So I can imagine this has a great deal of benefits if it were to come into practice. So I guess, what actual stage is the research at now, how far away do you imagine we are from that being a therapeutic use?
Robin - The quick answer is that now we’re beginning to understand the mechanisms, it opens various approaches, theoretical and otherwise, to treatment and that could be many years ahead. But there’s been an intensive effort made to look at therapies for hypertension and now as we look at the various treatments that have been tried or being given in trials in early stages, there are some that we feel might be relevant to the basic process that’s occurring and we hope our findings will be an encouragement to these people and eventually pharmaceutical companies to follow this up.
Meera - Robin Carroll, Emeritus Professor of Haematology from the University of Cambridge.