PHILADELPHIA--Despite its name, not all "good" cholesterol may be good for everyone. In patients whose coronary arteries are clogged with plaques, as much as half of the high density lipoprotein (HDL), the particle that carries good cholesterol, is chemically altered so that it can't combat the buildup of cholesterol deposits, researchers reported here 25 August at a meeting of the American Chemical Society. The new work is expected to lead to improved heart disease diagnostics, as well as to novel drugs that prevent atherosclerosis by blocking the damage to HDL.
The research is an offshoot of efforts to find better ways to track heart disease risk. Last year, Stanley Hazen, a physician and chemist at the Cleveland Clinic in Ohio, and colleagues identified two chemical fingerprints that were far better than existing markers at pinpointing a person's risk of heart disease. The first of these markers was myeloperoxidase (MPO), a key enzyme that immune cells use to fight microbial invaders. Among patients seeking emergency care for chest pain, those with high MPO levels had a higher near-term risk of heart attacks, bypass surgery, or death. The second was a suite of proteins modified by adding a chemical group called nitrotyrosine, a reaction that can be carried out by MPO and other compounds. Patients with high levels of these nitrotyrosine-modified proteins were more likely to have atherosclerosis. Hazen's group wanted to know if a particular protein was more likely than others to be hit with nitrotyrosine.
They discovered that MPO's favorite target is apolipoprotein A-1 (apoA-1), the primary protein in HDL. And when they looked at blood samples from 90 patients, half with and half without cardiovascular disease, they found that patients with lots of modified apoA-1 were 16 times more likely to belong to the group with heart disease. By contrast, currently used clinical markers--cholesterol and C-reactive protein--are far worse at predicting disease. The findings also appear in the current Journal of Clinical Investigation. Hazen suggests that when MPO reacts with apoA-1, it modifies the protein at one or more key sites, interfering with the protein's ability to ferry cholesterol out of cells and eventually leading to atherosclerosis.
"This is pretty exciting," says Ian Blair, a disease biomarker expert at the University of Pennsylvania in Philadelphia. "He seems to have a biomarker that is far better than existing biomarkers for cardiovascular disease." In addition, he adds, for the first time the new work lays out a clear molecular mechanism that explains why high HDL levels may not always be protective against heart disease. Hazen says his group and others are already at work on MPO-tracking diagnostics, and drug companies are looking for compounds to inhibit MPO and prevent the HDL deactivation.