Lifestyle or diet is not always to blame when someone develops arteriosclerosis. A mutation in the blood cell genome can also significantly increase the risk of such vascular calcification, as researchers have discovered. If one of the guardian genes in the genome is altered by these mutations, this leads to an abnormal proliferation of immune cells in the blood vessel walls – and this in turn promotes the deposition of plaques.
Arteriosclerosis, technically atherosclerosis, is a real widespread disease – and one of the most common causes of cardiovascular diseases. It occurs when cholesterol and other blood fats build up in the walls of blood vessels, causing chronic inflammation and wall damage. This promotes the thickening of the vessel walls and the deposition of hardened plaque. Typical risk factors for atherosclerosis include high blood pressure, smoking, advanced age and high blood lipid levels.
Copy errors in the blood stem cells
But there is also a risk factor that is independent of a healthy or unhealthy lifestyle, as discovered by Yale University’s Seyedeh Zekavat and her colleagues. For their study, they investigated whether blood stem cell mutations acquired over the course of life play a role in vascular calcification. Given the hundreds of thousands of blood cells that produce these stem cells in our bodies every day, such DNA copying errors are inevitable
“Such mutations are relatively common even in healthy older people; at least ten percent of all people over the age of 70 are affected,” explain Zekavat and her team. However, it was previously unclear whether some of these random DNA changes can also increase the risk of arteriosclerosis. For this reason, the research team first used the genome data of 50,115 test persons to examine whether certain blood stem cell mutations occur more frequently in arteriosclerosis patients.
Mutation in the guardian gene increases the risk
And indeed: there was a striking connection between mutations in the so-called guardian gene p53 and an increased risk of atherosclerosis. The p53 protein produced by this gene plays a crucial role in suppressing tumors and eliminating potentially malignant cells. It is therefore considered an important protective mechanism once morest cancer. Previous studies have shown that mutations of this gene in blood cells significantly increase the risk of blood cancer.
The new results reveal that this guardian gene is apparently also important for protection once morest atherosclerosis: “We found that carriers of acquired mutations in the p53 gene have an increased risk of atherosclerosis and coronary artery disease,” reports co-author José Fuster National Research Center for Vascular Diseases in Madrid. “This effect was independent of established risk factors such as high blood pressure or elevated cholesterol levels.”
More immune cells in the vessel walls
In order to find out why and how the p53 mutations promote vasoconstriction, the researchers carried out additional studies with mice. In these, they switched off the p53 gene and then analyzed how this affects blood formation and blood vessels at the cellular level. It turned out that in mice with a deactivated p53 gene, plaques formed more quickly in the arteries, and the thickening of the vessel walls was also more pronounced. At the same time, the density of immune cells in the vessel walls and plaques increased – an indication of increased inflammatory processes.
The team observed something similar when they transplanted bone marrow cells with this mutation into the mice: the higher the proportion of blood stem cells with a disrupted p53 gene, the faster and more severely the animals developed atherosclerosis. “This confirms that the p53 mutation in blood stem cells is directly involved in the disease,” say Zekavat and her colleagues.
Additional risk factor in the elderly
According to the researchers, this explains why the risk of atherosclerosis also increases in older people who actually live a healthy life and do not have any common risk factors: the mutations in their blood stem cells that have accumulated over the course of their lives disrupt the guard function of the p53 gene and promote vascular disease. “Our combination of observations in humans with experimental studies in mice provides solid evidence that this mutation increases the risk of cardiovascular disease,” says Fuster.
Knowledge of this new mechanism might in future help to improve the diagnosis and treatment of patients who are particularly at risk. “One might use this to develop personalized strategies once morest the consequences of such mutations,” explains Fuster’s colleague Nuria Matesanz. (Nature, 2023; two: 10.1038/s44161-022-00206-6)
Quelle: Nature, National Center for Cardiovascular Research