Researchers discover how "bad cholesterol" enters the arteries

Researchers at UT Southwestern determined how circulating "bad cholesterol" penetrated the artery walls to cause plaque that narrowed blood vessels and caused heart attacks and strokes.

Since low-density lipoproteins, or LDL, the entry of cholesterol into the arterial wall are at the origin of the development of atherosclerosis or hardening of the arteries, and atherosclerosis causes heart attacks and stroke, future treatments to prevent this process could help reduce the occurrence of these lesions. threatening conditions, said Dr. Philip Shaul, lead author of the study published online today at Nature.

According to recent statistics from the American Heart Association (AHA), cardiovascular disease is the leading cause of death in the world and coronary heart disease (which is the cause of heart attacks) and strokes account for more than 60% cardiovascular deaths in the United States.

The study reveals for the first time how a protein called SR-B1 (abbreviation for class B receptor receptor, type 1) routes LDL particles into and through the endothelial cells that line the arteries. The study also revealed that a second protein called cytokinesis 4 dedicator, or DOCK4, associates with SR-B1 and is necessary to the process.

In the early stages of atherosclerosis, LDLs that have entered the artery wall attract and are engulfed by important immune system cells called macrophages that ingest or "eat" LDL particles. . Macrophages loaded with LDL become foam cells that promote inflammation and promote the development of atherosclerotic plaques.

The plates narrow the artery and may become unstable. Rupturing plaques can activate blood clotting and block blood flow to the brain or heart, resulting in a stroke or heart attack. In studies in mice with high cholesterol levels, the researchers determined that suppression of SR-B1 from endothelial cells lining the blood vessels resulted in significantly less LDL in the arterial wall, fewer foam cells and atherosclerotic plaques significantly smaller.

"At the beginning of this work, it was surprisingly unknown how LDLs enter the artery wall to cause cardiovascular disease," said Dr. Shaul, director of the Center for Pulmonary and Vascular Biology. UT Southwestern. "The paper's findings resolve this mystery and contradict the earlier assumption of many scientists that LDL simply enters sites of lesions or disruption of the unique endothelial cell layer that serves as a protective barrier to the wall of the body. # 39; artery. "

In their studies, the researchers compared the abundance of SR-B1 and DOCK4 in the aortic areas of mice prone to plaque formation compared to areas less likely to become affected. atherosclerosis. They found higher levels of SR-B1 and DOCK4 in disease-prone areas long before atherosclerotic plaque formation. This finding suggests that atherosclerotic lesions may be more common in some arteries because of the increased presence of SR-B1 and DOCK4 in the region, said Dr. Shaul, vice president of research at UTSW and professor of pediatrics, Associate Chair, Associates First Capital Corporation. Pediatrics.

To determine whether these findings could be applied to individuals, the researchers examined data on atherosclerotic and normal human arteries in three independent databases maintained by the National Institutes of Health (NIH). In all three databases, SR-B1 and DOCK4 were more abundant in atherosclerotic arteries than in normal arteries.

The researchers are currently exploring the possibility of using gene therapy to turn off or reduce the function of SR-B1 or DOCK4 in the endothelial cells lining the arteries to prevent atherosclerosis, said Dr. Shaul.

"If you could develop an inhibitor drug of SR-B1 or DOCK4, or a gene therapy that would inhibit them in endothelial cells, you could potentially reduce atherosclerosis and thereby reduce the incidence of coronary heart disease." , heart attacks and strokes ". he said. "Such strategies would complement current treatments reducing circulating LDL and would be particularly useful in situations where LDL reduction is difficult."