In atherosclerosis, fatty deposits form in blood vessel walls, narrowing and eventually rupturing or blocking them. It is one of the largest causes of death. The majority of efforts to treat atherosclerosis are focused on reducing the input of LDL cholesterol. This means statins and other, more recent approaches to lower levels of LDL cholesterol in the bloodstream, such as PCSK9 inhibitors. It is possible to reduce blood cholesterol to very low levels indeed, far below normal, and this actually has comparatively little effect on existing atherosclerotic lesions. Patients still die. The disease still progresses, just more slowly.
Atherosclerosis isn't a condition of cholesterol, for all that this is how it largely discussed in the medical profession, but rather a condition in which the macrophages responsible for clearing cholesterol from blood vessel walls become dysfunctional. The focus should be on the macrophages. Nonetheless, the research community remains largely focused on LDL. The work here is illustrative of attempts to find yet more ways to reduce LDL cholesterol in blood vessel walls, this time somewhat more specifically than by simply lowering levels everywhere. Still, I suspect it will be unlikely to produce benefits significantly greater than those of PCSK9 inhibitors and their general reduction in LDL cholesterol in the bloodstream.
Since low-density lipoprotein, or LDL, cholesterol entry into the artery wall drives the development of atherosclerosis, or hardening of the arteries, and atherosclerosis leads to heart attacks and strokes, future treatments preventing the process may help decrease the occurrence of these life-threatening conditions. A new study reveals for the first time how 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. The study also found that a second protein called dedicator of cytokinesis 4, or DOCK4, partners with SR-B1 and is necessary for the process.
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 studies of mice with elevated cholesterol, 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 that were considerably smaller.
In their studies, the researchers compared SR-B1 and DOCK4 abundance in areas of the mouse aorta that are prone to plaque formation compared with 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 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.