Gene That Promotes Atherosclerosis Found

Gene That Promotes Atherosclerosis Found
Credit: 7activestudio / Getty Images

Atherosclerosis, the accumulation of plaque inside artery walls, can lead to heart attacks and strokes. There are many factors that can contribute to the weakening of the arteries and increasing deposits of fat and cholesterol, including conditions such as high cholesterol, diabetes, high blood pressure, and obesity. However, a new study by scientists at Washington University School of Medicine in St. Louis reveals a gene that potentially plays a role in coronary artery disease independent of these conditions.

Their findings are published in the journal Science Translational Medicine in a paper titled, “SVEP1 is a human coronary artery disease locus that promotes atherosclerosis.”

”A low-frequency variant of sushi, von Willebrand factor type A, EGF, and pentraxin domain-containing protein 1 (SVEP1), an extracellular matrix protein, is associated with risk of coronary disease in humans independent of plasma lipids,” wrote the researchers. “Despite a robust statistical association, if and how SVEP1 might contribute to atherosclerosis remained unclear. Here, using Mendelian randomization and complementary mouse models, we provide evidence that SVEP1 promotes atherosclerosis in humans and mice and is expressed by vascular smooth muscle cells (VSMCs) within the atherosclerotic plaque.”

Researchers discovered that the gene—called SVEP1—makes a protein that drives the development of plaque in the arteries. In mice, animals missing one copy of SVEP1 had less plaque in the arteries than mice with both copies.

Using mouse models and evaluating human genetic data, the researchers observed that genetic variation influencing the levels of this protein in the body correlated with the risk of developing plaque in the arteries.

“Cardiovascular disease remains the most common cause of death worldwide,” said cardiologist Nathan O. Stitziel, M.D., Ph.D., an associate professor of medicine and of genetics. “A major goal of treatment for cardiovascular disease has appropriately been focused on lowering cholesterol levels. But there must be causes of cardiovascular disease that are not related to cholesterol—or lipids—in the blood. We can decrease cholesterol to very low levels, and some people still harbor residual risk of future coronary artery disease events. We’re trying to understand what else is going on, so we can improve that as well.”
The researchers demonstrated that the protein is a complex structural molecule and is manufactured by vascular smooth muscle cells. The protein was observed to drive inflammation in the plaques in the artery walls and to make the plaques less stable.

“In animal models, we found that the protein induced atherosclerosis and promoted unstable plaque,” explained co-first author In-Hyuk Jung, PhD, a staff scientist at Stitziel’s lab. “We also saw that it increased the number of inflammatory immune cells in the plaque and decreased collagen, which serves a stabilizing function in plaques.”

SVEP1 is required for early development of the embryo, however, removing the protein in adult mice did not appear to be harmful according to the researchers.

Their findings pave a new path for potential coronary artery disease treatments and may lead to further strategies that target or block the gene.