Study Title:

Rising Blood Pressure Induced by Oxidised Angiotensinogen

Study Abstract

Blood pressure is critically controlled by angiotensins1, which are vasopressor peptides specifically released by the enzyme renin from the tail of angiotensinogen—a non-inhibitory member of the serpin family of protease inhibitors2, 3. Although angiotensinogen has long been regarded as a passive substrate, the crystal structures solved here to 2.1 Å resolution show that the angiotensin cleavage site is inaccessibly buried in its amino-terminal tail. The conformational rearrangement that makes this site accessible for proteolysis is revealed in our 4.4 Å structure of the complex of human angiotensinogen with renin. The co-ordinated changes involved are seen to be critically linked by a conserved but labile disulphide bridge. Here we show that the reduced unbridged form of angiotensinogen is present in the circulation in a near 40:60 ratio with the oxidized sulphydryl-bridged form, which preferentially interacts with receptor-bound renin. We propose that this redox-responsive transition of angiotensinogen to a form that will more effectively release angiotensin at a cellular level contributes to the modulation of blood pressure. Specifically, we demonstrate the oxidative switch of angiotensinogen to its more active sulphydryl-bridged form in the maternal circulation in pre-eclampsia—the hypertensive crisis of pregnancy that threatens the health and survival of both mother and child.

From press release:

Scientists have discovered a mechanism which raises blood pressure in pre-eclampsia, a potentially deadly condition which occurs during pregnancy.

After 20 years of research, scientists from the University of Cambridge have now cracked the first step in the main process that controls blood pressure. Their findings, published in the journal Nature, are likely to have significant implications for the treatment of pre-eclampsia as well as high blood pressure (also known as hypertension).

Blood pressure is controlled by hormones called angiotensins, which cause the blood vessels to constrict. These hormones are released by the protein angiotensinogen. Until now, it was not understood how this occurred.

Dr Aiwu Zhou, a British Heart Foundation (BHF) Fellow at the University of Cambridge, who made the breakthrough, said: "Although we primarily focused on pre-eclampsia, the research also opens new leads for future research into the causes of hypertension in general."

To make the discovery, the researchers solved the structure of angiotensinogen with the help of an extremely intense X-ray beam produced by Diamond Light Source, the UK synchrotron. Their results revealed that the protein is oxidised and changes shape to permit ready access to angiotensinogen by an enzyme, renin. Renin cuts off the tail of the protein to release the hormone angiotensin, which then raises blood pressure.

Taking their lab results into the clinic at the University of Nottingham, the research team showed that the amount of oxidised, and hence more active, angiotensinogen was increased in women with pre-eclampsia.

Professor Robin Carrell at the University of Cambridge, who led the 20-year research project, explained: "During pregnancy oxidative changes can occur in the placenta. These changes, the very ones we have found stimulates the release of the hormone angiotensin and lead to increased blood pressure, can arise as the circulation in the placenta readjusts the oxygen requirements of the growing foetus with the delivery of oxygen to the placenta from the mother."

Drugs currently used to treat high blood pressure -- such as ACE inhibitors -- focus on the later stages of the mechanism that controls blood pressure. The latest findings, which give insight into the previously mysterious early stages of the regulation process, provide scientists with new opportunities to research novel treatments for hypertension.

Professor Peter Weissberg, Medical Director of the BHF, which largely funded the study, said: "Every year in the UK pre-eclampsia is responsible for the deaths of around six women and several hundred babies. This research is of the highest quality and offers real hope for developing strategies to prevent or treat this dangerous condition by targeting the process that these scientists have identified. And of course, although the researchers only looked at pre-eclampsia in this study, similar strategies may be useful for those people with high blood pressure that is not effectively controlled by current medicines."

High blood pressure frequently affects pregnancy. However, in 2-7 per cent of pregnancies this develops into pre-eclampsia, which threatens the health and survival of both the mother and child. In Britain, it affects about one in 20 women during pregnancy, and every year 50,000 women and 500,000 infants die globally as a result of pre-eclampsia. There is no treatment for pre-eclampsia and often the mother is either induced early or undergoes a Caesarean.

The research was largely funded by the British Heart Foundation, with additional funding provided by the Medical Research Council, the Wellcome Trust and the Isaac Newton Trust.

Study Information

Aiwu Zhou, Robin W. Carrell, Michael P. Murphy, Zhenquan Wei, Yahui Yan, Peter L. D. Stanley, Penelope E. Stein, Fiona Broughton Pipkin, Randy J. Read.
A redox switch in angiotensinogen modulates angiotensin release.
2010 October
Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK.

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