Cholesterol-Ferrying Proteins Promote Buildup of Cardiovascular Plaque

Despite contributing to heart attacks and strokes, the migration of “bad” cholesterol into artery walls has been poorly understood. The bad cholesterol, or low-density lipoprotein (LDL), has been thought to accumulate passively, leaking through gaps in the single-cell-thick endothelium that lines blood vessels. LDL, however, appears to be conveyed into artery walls by the body’s own proteins. LDL accumulation, then, is the result of an active process. If this process could be disrupted, perhaps with new drugs or via gene therapy, fewer people may succumb to cardiovascular disease, which is currently the leading cause of death worldwide.

The LDL-transporting mechanism was discovered by scientists based at UT Southwestern Medical Center. These scientists, led by Philip W. Shaul, MD, found that a protein called SR-B1 (short for scavenger receptor class B, type 1) ferries LDL particles into and then across the endothelial cells that line arteries. Shaul and colleagues also found that a second protein called dedicator of cytokinesis 4, or DOCK4, partners with SR-B1 and is necessary for the process.

Additional details appeared April 24 in the journal Nature, in an article titled, “SR-B1 drives endothelial cell LDL transcytosis via DOCK4 to promote atherosclerosis.” This article describes how experiments in mice showed that SR-B1 in endothelial cells mediates the delivery of LDL into arteries and its accumulation by artery wall macrophages, thereby promoting atherosclerosis.

“LDL particles are colocalized with SR-B1 in endothelial cell intracellular vesicles in vivo, and transcytosis of LDL across endothelial monolayers requires its direct binding to SR-B1 and an eight-amino-acid cytoplasmic domain of the receptor that recruits the guanine nucleotide exchange factor dedicator of cytokinesis 4 (DOCK4),” the article’s authors wrote. “DOCK4 promotes internalization of SR-B1 and transport of LDL by coupling the binding of LDL to SR-B1 with activation of RAC1.”

In the early stages of atherosclerosis, LDL that has entered the artery wall attracts and is engulfed by important immune system cells called macrophages that ingest, or “eat,” LDL particles. LDL-laden macrophages become foam cells that promote inflammation and further the development of atherosclerotic plaques.

The plaques narrow the artery and can become unstable. Plaques that rupture can activate blood clotting and block blood flow to the brain or heart, resulting in a stroke or heart attack.

In the current study, the investigators determined that deleting SR-B1 from the endothelial cells lining blood vessels resulted in far less LDL entering the artery wall. Fewer foam cells formed, and atherosclerotic plaques were considerably smaller.

“The expression of SR-B1 and DOCK4,” the article’s authors added, “is increased in atherosclerosis-prone regions of the mouse aorta before lesion formation, and in human atherosclerotic arteries when compared with normal arteries.”

Essentially, the researchers compared SR-B1 and DOCK4 abundance in areas of the mouse aorta that are prone to plaque formation, with SR-B1 and DOCK4 abundance in regions less likely to become atherosclerotic. They found higher levels of SR-B1 and DOCK4 in the disease-prone regions long before atherosclerotic plaques formed. This finding, Shaul noted, suggests that atherosclerotic lesions may be more common in particular artery sites because of more SR-B1 and DOCK4 present there.

To determine if these findings might apply to people, the researchers reviewed data on atherosclerotic and normal arteries from humans 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 compared with normal arteries.

The researchers are now exploring the possibility of using gene therapy to turn off or reduce the function of SR-B1 or DOCK4 in the endothelial cells that line arteries in order to prevent atherosclerosis.

“If you could develop a drug that inhibits SR-B1 or DOCK4, or a gene therapy that silences them in endothelial cells, you could potentially decrease atherosclerosis and, hence, reduce the incidence of coronary artery disease, heart attack, and stroke,” Shaul asserted. “Such strategies would complement current treatments that lower circulating LDL and be particularly valuable in situations in which LDL lowering is challenging.”