According to UTHealth Houston researchers, a novel molecular pathway has been identified to explain how individuals in their 30s with normal cholesterol levels and no other risk factors can develop coronary artery disease as a result of a mutation in the gene ACTA2.
The study was presented for publication in the European Heart Journal.
“The quality ACTA2 codes a particular protein that doesn’t have anything to do with cholesterol,” said Dianna Milewicz, MD, Ph.D., senior creator of the review and teacher and head of the Division of Clinical Hereditary Qualities at McGovern Clinical School at UTHealth Houston. “It was surprising to discover that individuals with the gene mutation had excessive atherosclerosis at an early age and had no risk factors.”
Humans with a number of ACTA2 mutations are more likely to develop coronary artery disease in their 30s or younger, according to a 2009 Milewicz-led study.
“The ACTA2 gene encodes a protein that has nothing to do with cholesterol. It was surprising to discover that those with the DNA mutation had excessive atherosclerosis at such a young age and without any risk factors.”
Dianna Milewicz, MD, Ph.D., senior author of the study and professor .
An accumulation of fats, cholesterol, and other substances in and on the artery walls is called atherosclerosis. Most people don’t know they have it until they have a heart attack or stroke, but it can get worse over time. High cholesterol, high blood pressure, diabetes, smoking, obesity, inactivity, and a diet high in fat are all traditional risk factors for atherosclerosis.
ACTA2 is normally found in the smooth muscle cells, which line the courses and permit the corridors to agree to control circulatory strain and flow. Milewicz and her colleagues discovered that the mutation causes the protein coded by this gene to not fold correctly. This stress causes the smooth muscle cells to produce more cholesterol internally, regardless of blood cholesterol levels, resulting in the formation of atherosclerotic plaque.
“This finding is extraordinary in that we tracked down a totally new pathway to atherosclerosis. It explains why we have known for a long time that statins prevent heart attacks even in people with normal blood cholesterol levels. “The statins block the cholesterol made by the stressed smooth muscle cells in people with ACTA2 mutations,” Milewicz, who holds the President George Bush Chair in Cardiovascular Medicine at McGovern Medical School, said.
“The cells in the artery wall were stressed in our study by the mutant protein produced by the ACTA2 mutation, but there are numerous other factors that can stress cells. We are currently focusing on risk factors for coronary artery disease, such as high blood pressure, which would also put stress on the cells and activate this novel coronary artery disease pathway.
The accumulation of calcium in the arteries is one of the outcomes of stress in smooth muscle cells that is associated with atherosclerosis.
“A useful early diagnostic tool for monitoring the development of early atherosclerosis in people with ACTA2 mutations could be cardiac calcium imaging. Milewicz stated, “This would enable physicians to decide at what age to begin prescribing statins to these patients.”
The researchers induced atherosclerosis in a genetically engineered mouse with a specific ACTA2 mutation and fed the mice a diet high in cholesterol. They found that these mice had significantly more atherosclerosis than normal mice that were treated similarly.
Pravastatin, a member of the statin class of medications used to lower blood cholesterol, was found to be able to reverse the mice’s increased atherosclerosis, according to the study. The scientists affirmed that an equivalent sub-atomic pathway is enacted in smooth muscle cells segregated from a human patient with an ACTA2 transformation.
By lowering cholesterol in the blood, statins prevent coronary artery disease. Simultaneously, the greater part of respiratory failures happen in obviously solid people with normal or low levels of plasma LDL cholesterol. In patients with normal cholesterol levels, statins also lower the risk of heart attacks.
More information: Kaveeta Kaw et al, Smooth muscle α-actin missense variant promotes atherosclerosis through modulation of intracellular cholesterol in smooth muscle cells, European Heart Journal (2023). DOI: 10.1093/eurheartj/ehad373
