Fractalkine - a new drug target to treat atherosclerosis

20 December 2014        

Researcher

Researchers from the University of Oxford have recently shown how a small protein called fractalkine may help increase the furring of arteries. 

Developing drugs to target and reduce the amount of fractalkine in the blood could be a new way to slow furring of the arteries, known as atherosclerosis, and reduce the risk of heart attacks and strokes.

Atherosclerosis occurs when the body’s immune system attacks fat trapped in artery walls. Certain types of fast response white blood cells invade the artery walls in pursuit of the trapped fat and this causes inflammation.  More white blood cells are attracted to the inflammation and also invade. This cycle continues, causing the build-up of furring, or atheroma, in the artery wall in a processes called atherogenesis and forms an atherosclerotic plaque.

Atherosclerotic plaques are dangerous because they narrow arteries, which can prevent oxygenated blood from getting where it is needed. It can also rupture from the artery wall and form clots that block blood vessels altogether, leading to heart attacks and strokes. 

Growing Plaques

The new research, led by Professor David Greaves, suggests that fractalkine may help these plaques develop and grow by enabling a type of white blood cell, called monocytes, to survive when inside atherosclerotic plaques. Once inside, monocytes can change into other types of white blood cells which are responsible for increasing the size of plaques and recruiting more white blood cells to the area, exacerbating the problem.

Professor David Greaves said:

“Our work shows how a protein, called fractalkine, can act as a survival factor that enables more white blood cells to survive in the body and also in atherosclerotic plaques. 

“Designing drugs to target the fractalkine protein may be a new way in which we can reduce the risk of coronary heart disease, heart attack and stroke caused by atherosclerosis by slowing the formation or growth of atherosclerotic plaques.”

The Experimental Process

targeting fractalkine is a promising approach to design a new medicine to combat coronary heart disease

Professor Jeremy Pearson
BHF Associate Medical Director

In a series of experiments researchers exposed human monocytes to an environment with very few nutrients and little oxygen similar to conditions in atherosclerotic plaques, and as expected most of them died in this harsh environment. However, when researchers added a small amount of fractalkine, 70 per cent of these cells were able to live. This work was carried out in a petri dish, but if these surviving cells were within an atherosclerotic plaque they may now be able to differentiate causing plaques to grow.

In the surviving cells, fractalkine was shown to reduce the amount of harmful molecules known as reactive oxygen species that, ordinarily, would kill the monocytes. Fractalkine lowered the amount of reactive oxygen species inside cells to a safe level, allowing them to survive. 

Designing drugs to bind to fractalkine could inhibit the ability of monocytes to survive in atherosclerotic plaques and reduce their formation and growth.

While this work is in its very early stages Professor Greaves is already excited about the potential of fractalkine:

“The next step for this research is to identify a safe way to reduce the amount of fractalkine in the blood in patients with a high risk of coronary heart and look for beneficial effects on atherosclerotic plaques in arteries. 

"This will be challenging but it could be a novel way to improve a currently incurable and life threatening condition.”

Professor Jeremy Pearson, Associate Medical Director at the BHF, which helped fund the research, said:

“The results of this study on human white blood cells strengthens the idea that targeting fractalkine is a promising approach to design a new medicine to combat coronary heart disease. But more research will be required before this avenue can be explored in patients.”