The protein behind heart attack plaques

11 February 2020

Interview with 

Ellie Tzima, Oxford University

BLOOD-VESSEL

red blood cells cascading through a blood vessel

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Scientists have found an important trigger that causes arteries to furr up. This is the disease process called atherosclerosis, where arteries become narrowed by the formation of fatty plaques in the vessel lining. These cause heart attacks and strokes. But how these plaques form in the first place is still a mystery. Now scientists at Oxford University have found that a molecule called Plexin D1, probably starts the whole process off. Adam Murphy heard how from Ellie Tzima...

Ellie - It's been known since the 1960s that plaques are very focal in their distribution, which means that not all arteries and all regions of the arteries will develop a plaque. Some regions are prone to development of a plaque, whereas others are protected and it has to do with the type of blood flow that these regions experience. For example, in areas such as curvatures or bifurcations where vessels split into two, there's irregular blood flow patterns where whirls and eddies form and the endothelial cells, the cells that line blood vessels in those areas, sense this type of disturbed blood flow and they respond accordingly. They start signaling pathways that will ultimately lead to the formation of a plaque.

Adam - This is what you've been looking into isn't it? What first starts these things? Could you tell us a little about that?

Ellie - Yes, so we discovered the molecular first responder. Basically the molecule that detects these disturbances in blood flow and responds by encouraging the formation of plaques which as I mentioned can lead to these serious complications. We've discovered the molecule that is able to detect the earliest changes and lead to, eventually, the formation of a plaque.

Adam - What is this molecule?

Ellie - It's called Plexin D1. It's a molecule that has been studied quite a bit in neurobiology, especially in its role as a guidance receptor, to feel what the environment is like, and then they transmit that information to the main part of the cell.

Adam - What is it doing then in blood vessels? What's it doing differently and how does it start this plaque formation?

Ellie - What we think is happening is that Plexin D1 has a universal ability to sense mechanical force, whether it is in a neuron or in an endothelial cell or blood vessel cell. And it is then able to transmit that information inside the cell that will initiate a number of pathways that will ultimately result in inflammation, and that inflammation in collaboration with risk factors will ultimately lead to formation of a plaque.

Adam - Then is there potentially a treatment here?

Ellie - Plexin D1 has two structures. One of them is a sort of a closed ring-like structure and the other one is an open chair-like structure. We found and we showed that in fact it is the open conformation, this chair-like conformation of the molecule, that allows it to sense blood flow and transmit those signals inside the blood vessel to ultimately signal for formation of a plaque. And what we're doing right now is we're screening drug libraries to try and find a drug that specifically blocks only this chair-shaped Plexin D1 conformation, to specifically disrupt only this pathological signaling that leads to the formation of an atherosclerotic plaque.

Adam - Would this be then a preventative measure or could it treat people who already have it?

Ellie - It could be both. Ideally we want to in the future, be able to block even before they start. That would be the aim.

Adam - You mentioned you're looking through drug libraries, but you also said this thing works in the brain, so would blocking off its function not potentially have some pretty serious side effects?

Ellie - Yes, that's a great point. And this is something that we need to look at, but this is very early stages. We've just discovered that this molecule has this function in regulating atherosclerosis development. So work at the moment in the lab, and I'm sure others will follow, will be to examine what exactly Plexin is doing in the neuronal system, what its function is in the cardiovascular system in terms of the protective effects of blood flow. because blood flow is not all bad. Really there's a long way to go, but we're very, very excited to look further into this.

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