Atherosclerosis involves the slow build-up of fatty material, white blood cells and connective tissue inside an artery wall, to form a ‘plaque’. If the plaques are sufficiently large to prevent adequate blood flow to the heart, patients experience angina. More devastatingly, though, some plaques are unstable and can crack (rupture). This attracts blood cells called platelets that within minutes form a clot in the artery – the most common cause of a heart attack.

What causes plaque rupture?

Atherosclerotic plaques are normally stabilised by a fibrous ‘cap’, consisting of smooth muscle cells that produce strengthening proteins like collagen. But the fibrous caps also contain enzymes, known as matrix metalloproteinases (MMPs), that can degrade collagen, so they could potentially cause plaque rupture. Conversely, plaque rupture could be prevented by increasing the number of smooth muscle cells in the fibrous cap so that it doesn’t crack.

So a major research focus of the Bristol Heart Institute is elucidating the role of the MMPs and the mechanisms causing smooth muscle cell growth in order to understand plaque rupture. Until recently this was difficult, owing to the lack of suitable experimental models. But now researchers have developed a unique model using mice that produce unstable plaques in their arteries after eight weeks on a high-fat diet. Experiments were conducted in mice, each with a different MMP ‘knocked out’. Knocking out some MMPs made plaques more stable, as expected; however, other MMP knock-outs actually made plaques more fragile, implying that these played a particular role in plaque stability instead. These findings caused a major pharmaceutical company to refocus its MMP-related drug development programme.

But cells in the atherosclerotic plaque secrete enzymes other than MMPs that can contribute to plaque rupture. Researchers are therefore using methods that scan all the genes expressed in plaque cells to find out what makes a plaque unstable. If genes could be found that serve as markers in blood to indicate whether someone has an unstable plaque, then that patient could be treated before suffering a heart attack.

Guarding against thrombosis

Central to thrombosis are platelets, the smallest cells in the blood, whose normal role is to stop bleeding. Platelets are very active and sticky, although their ability to stick together is regulated by events inside the cell, known as a signalling pathway. This signalling involves enzymes called protein kinases that eventually trigger clotting. One of these enzymes, protein kinase C, seems particularly important in this process, and researchers are investigating whether protein kinase C can be used as a novel target to prevent blood clotting following, for example, rupture of atherosclerotic plaques.

The Bristol Heart Institute