Drugs that target a protein that regulates cholesterol levels in the blood may also be able to reduce the risk of developing thrombosis, a type of blood clot that can lead to heart attack or stroke, researchers at the University of Reading in the UK were surprised but delighted to discover.

Professor Jon Gibbins, Director of the Institute for Cardiovascular and Metabolic Research (ICMR) at the University, and colleagues, showed that modifying the effect of the liver X receptor (LXR) protein, a transcription factor protein that regulates levels of cholesterol, fatty acid, and glucose, reduced the size and stability of blood clots in laboratory mice.

You can read about the study in a first edition paper prepublished online on 16 March in the journal Blood.

Gibbins told the BBC they were excited by this potentially important discovery:

“While blood clotting is essential to prevent bleeding, inappropriate clotting within the circulation, known as thrombosis, is the trigger for heart attacks and strokes.”

Heart attacks and strokes kill more people in the UK every year than any other disease, he said.

Companies are already investigating the potential of using LXR as a target for new cholesterol-busting drugs.

Now this study opens the possibility for using LXR as an anti-thrombotic target.

The British Heart Foundation told the BBC this was an exciting discovery that could lead to more effective treatments to prevent heart attacks and strokes.

Gibbins and the rest of the team at the ICMR were looking into the molecular mechanisms of blood platelets and how they lead to clots when they decided to investigate the role of LXR in platelets.

They wrote in their background information that they already knew certain LXR agonists, that is molecules that activate particular responses in proteins that control cell functions, “have athero-protective properties independent of their effects on cholesterol metabolism”.

So they speculated perhaps platelets play a role in mediating the clot-busting effects of certain LXR agonists and decided to look more closely at the mechanisms involved.

They pinpointed one agonist, called GW3965, and showed it caused “LXR to associate with signaling components proximal to the collagen receptor, GPVI, suggesting a potential mechanism of LXR action in platelets that leads to diminished platelet responses.”

Then, using live lab mice, they found that GW3965 had anti-thrombotic effects: the result was smaller and less stable clots.

They concluded that:

“The athero-protective effects of GW3965, together with its novel anti-platelet/thrombotic effects indicate LXR as a potential target for prevention of athero-thrombotic disease.”

About 30,000 people die in the UK every year after developing a blood clot.

Gibbins and his team receive grants from Medical Research Council, the Biotechnology and Biological Sciences Research Council, the British Heart Foundation and the Wellcome Trust to research ways to better understand the molecular mechanisms of blood platelets so as to help develop more effective ways to prevent and treat thrombosis.

“LXR as a novel anti-thrombotic target.”
Michael Spyridon, Leonardo A. Moraes, Chris I. Jones, Tanya Sage, Parvathy Sasikumar, Giovanna Bucci, and Jonathan M. Gibbins.
Blood, First Edition Paper, prepublished online 16 March 2011.
DOI 10.1182/blood-2010-09-306142

Additional source: BBC News.

Written by: Catharine Paddock, PhD