How a Genetic Mutation Can Cause Individuals with Normal Cholesterol Levels to Develop Coronary Artery Disease at a Young Age
Published:06 Aug.2023 Source:University of Texas Health Science Center at Houston
A 2009 study led by Milewicz found that a number of mutations in ACTA2 predispose humans to develop early onset (30s or younger) coronary artery disease. Atherosclerosis is a buildup of fats, cholesterol, and other substances in and on the artery walls. It can develop over time and most people don't know they have it until they suffer a heart attack or stroke.
ACTA2 is typically found in the smooth muscle cells, which line the arteries and allow the arteries to contract to control blood pressure and flow. Milewicz and her team found that protein coded by this gene is not folded correctly because of the mutation, and it triggers stress in the smooth muscle cell, which then forces the cell to make more cholesterol internally, regardless of the levels of cholesterol in the blood, driving atherosclerotic plaque formation.
One of the results of stress in smooth muscle cells associated with atherosclerosis is the deposition of calcium in the arteries. Using a genetically engineered mouse that contains a particular ACTA2 mutation and feeding the mice a diet rich in cholesterol, the researchers induced atherosclerosis and found that these mice have much more atherosclerosis than similarly treated mice normal mice. The study also found that the increased atherosclerosis could be reversed by treating the mice with pravastatin, a member of the statin group of drugs commonly prescribed to lower blood cholesterol. The researchers confirmed that same molecular pathway is activated in smooth muscles cells isolated from a human patient with an ACTA2 mutation. Statins prevent coronary artery disease by lowering the levels of cholesterol in the blood. At the same time, more than half of heart attacks occur in apparently healthy men and women with average or low levels of plasma LDL-cholesterol. Statins also reduce heart attack events in people with normal cholesterol levels.