Researchers at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) have shown that changes in the gene that creates the protein p53, known as the “Guardian of the Genome,” can contribute to the development of cardiovascular disease. This discovery was made in collaboration with institutes in the USA, the p53 protein helps to preserve the integrity of the genetic material within cells by regulating multiple cell functions in response to cellular stress.
It is known that every day an adult generates hundreds of thousands of blood cells, a process that inevitably leads to mutations in the progenitor cells responsible for the production.
A new study published in Nature Cardiovascular Research, led by José Javier Fuster, has found that acquired mutations in the p53 gene found in blood cells not only increase the risk of developing various types of cancer, including blood cancer but also accelerate the development of atherosclerosis, a leading cause of cardiovascular disease which is the leading cause of death worldwide and puts a significant burden on healthcare systems. The study is conducted by a team at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) in collaboration with institutes in the USA.
The authors investigated sequencing data from the blood cells of more than 50,000 patients while collaborating with the teams headed by Derek Klarin at Stanford University, Pradeep Natarajan at Massachusetts General Hospital, and Alexander Bick at Vanderbilt University.
The results showed “that carriers of acquired mutations in p53 had a higher risk of developing coronary heart disease and peripheral artery disease, and this effect was independent of established cardiovascular risk factors like hypertension or elevated blood cholesterol,” according to Dr. José Javier Fuster.
Based on these findings, the CNIC researchers performed functional experiments in animal models of atherosclerosis in which they introduced cells with p53 mutations.
The findings demonstrated that mice with these mutations acquired cardiovascular illness more quickly, mostly as a consequence of unusually high immune cell proliferation rates in arterial walls.
“This combination of observations in humans with experimental studies in animals provides solid evidence that these mutations increase the risk of developing cardiovascular disease,” adds Dr. Fuster.
These results “broaden our knowledge of how the acquisition of mutations in blood cells, a phenomenon called as clonal hematopoiesis, acts as a cardiovascular risk factor,” according to Dr. Valentn Fuster, CNIC General Director, President of Mount Sinai Heart, and physician-in-chief of The Mount Sinai Hospital.
The same group’s earlier research had previously shown in a 2021 article in The Journal of the American College of Cardiology (JACC) that a number of these mutations, including those that impact the TET2 gene, aid in the development of cardiovascular illnesses such atherosclerosis and heart failure.
Dr. José Javier Fuster said that the latest findings not only confirm prior research but also expand our findings to include mutations in p53 and the development of peripheral artery disease, a condition that is very common in the senior population.
The researchers emphasize that various gene mutations cause cardiovascular disease through various pathways.
Nuria Matesanz, a CNIC scientist and one of the study’s co-first authors, says, “In the future, this could be exploited to design personalized prevention strategies targeting the specific effects of different mutations.”
Source: 10.1038/s44161-022-00206-6
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