Cholesterol-releasing enzyme to reduce heart disease?
of heart-disease causing plaques by removing the cholesterol that
causes them to form.
The discovery could pave the way for the development of new therapeutic approaches to stop heart disease by addressing the imbalance between the influx and efflux of LDL cholesterol into atherosclerotic plaques that form in the coronary artery in response to high cholesterol levels. According to the World Health Organization (WHO), heart disease and stroke kill more than 17m people a year. The plaques that cause hear disease form when monocytes in the blood enter the artery wall and start to consume large amounts of LDL or 'bad' cholesterol, eventually becoming artery-clogging macrophage foam cells. In this latest research, published in the October issue of the Journal of Clinical Investigation, scientists from the Virginia Commonwealth University and Wake-Forest University School of Medicine describe how the cholesteryl ester hydrolase (CEH) enzyme plays a key role in limiting the growth of these plaques. "Currently the emphasis for managing heart disease is on reducing the "bad" cholesterol or LDL in the circulation," said Dr Shobha Ghosh of the Virginia Commonwealth University and lead author of the report. These approaches commonly involve the prescription of statins, such as Pfizer's Lipitor (atorvastatin) currently the world's biggest selling drug with 2006 sales of around $13bn (€9bn). "Our study demonstrates that if you can increase the removal of cholesterol from the plaques, even without changing the LDL levels, there is still a significant reduction in the plaques," she continued. After cholesterol uptake by the plaques, it is stored as a cholesteryl ester (CE). While this uptake is initially beneficial because it prevents free cholesterol toxicity, when too much is stored the plaques become 'foamy' and lead to arterial blockage. The primary mechanism for removing the cholesterol is via an extracellular accepter-mediated pathway that relies on the CEH enzyme to hydrolyse the cholesterol and enable it to be removed from the body as bile acid. The researchers note that "despite the obvious significance of cholesteryl ester hydrolysis in cellular free cholesterol efflux, limited efforts have bee directed toward manipulating this step as a potential target for pharmacological or genetic intervention" due to "the controversy surrounding the identity of neutral CEH". The researchers created a line of transgenic mice that had been spliced with the gene that codes for CEH. By feeding the mice on a high-fat and cholesterol-rich diet, the researchers showed that the enzyme increased the removal of cholesterol from the artery clogging cells and significantly reduced the size of the plaques and thus the chance of the developing heart disease. "These findings not only change the current thinking of managing heart disease but also clearly open avenues for the development of new therapies. By identifying CEH as a new therapeutic target, we expect that in the future patients with heart disease will have more options to aggressively treat heart disease," said Dr Ghosh.
