New molecule that relaxes blood vessels discovered

In an amazing piece of chemical sleuthing published in the leading scientific journal Nature, scientists at the Victor Chang Cardiac Research Institute and the University of Sydney have combined to discover a novel molecule that relaxes blood vessels during inflammation.

In an earlier study reported in Nature Medicine in 2010, the leader of the research, Professor Roland Stocker, showed a metabolite of the amino acid tryptophan, called kynurenine, causes blood vessels to dilate profoundly during sepsis. This results in the very low blood pressure characteristic of the condition, which, in turn, can cause multi-organ failure and death.

Following up from this observation, the team found that, in fact, the culprit that causes blood vessels to dilate was not kynurenine itself, but a precursor of kynurenine. But to identify this precursor took many additional years of research and very detailed and sophisticated chemical detective work.

Now for the first time, the researchers have identified the true nature of the blood vessel dilating substance.

The chemical detective work was carried out by Professor Stocker’s team with Professor Richard Payne and Dr Andrew Giltrap from the School of Chemistry at the University of Sydney. These researchers were able to chemically synthesise and characterise this mystery molecule.

They found it to be a novel molecule called cis-WOOH. Professor Stocker’s research team subsequently showed that the molecule was made by an enzyme called IDO that is present in blood vessels only during inflammatory conditions which converts the common amino acid tryptophan into cis-WOOH.

“By making and analysing cis-WOOH in the lab we were able to help to confirm its ability to cause blood vessels to relax under inflammatory conditions in biological systems.” Said Dr Andrew Giltrap. He also noted that, “It has been really exiting to be a part of such a large multi-disciplinary study and to know that chemistry is central to discoveries with profound biological significance.”

But it is an associated discovery – an evolutionary finding - that has Prof Stocker most excited  

During the course of their cis-WOOH experiments, the scientists identified that a molecule called singlet oxygen is required to convert tryptophan to cis-WOOH.

Singlet oxygen was previously thought to only be used in plants and micro-organisms, where it is formed via chemical reactions that require light and oxygen. The discovery now shows singlet oxygen to also be made in mammals, including humans, but without the need for light.

“The finding that singlet oxygen, a highly reactive molecule, can be produced in our body, means it likely has an important function …  otherwise why would evolution have allowed this to happen?” Prof Stocker said. “For me, that is the most exciting part of our work.”

“This pathway is very heavily studied in the context of cancer therapy and inflammatory conditions. So, one of the things we propose, very hypothetically, is that this molecule could potentially kill tumour cells ­– a stretch, but nevertheless an exciting hypothesis

“And our findings now provide the rationale for investigating this novel but potentially far-reaching proposition.”

The project, Prof Stocker noted, had been “all about endurance and tenacity”, involving many people from multiple institutes, universities and hospitals around Australia and in several other countries over the past decade.

“It spans the gamut of investigative approaches from synthetic chemistry, to analytical chemistry, biochemistry, molecular biology, physiology and then to pre-clinical work, involving an array of technologies – it’s pretty cool, and extremely rewarding, to actually be able to do that”.

The project has been funded in part by grants from NSW Health and the National Health and Medical Research Council, Australia, and also involved collaborations with scientists at the University of NSW,  and Monash, as well as universities in Tokyo (Japan), Nanjing (China) and Sao Paulo (Brazil), and also King’s College and the Rayne Institute, London.

The work, entitled Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation has been published in Nature.

This article was adapted from a full media release prepared by the Victor Chang Cardiac Research Institute.