Significant advances in the understanding of atherosclerosis
Now, for the first time, a link has been identified between mitochondria, inflammation and a pair of genes thought to be a risk factor for the development of atherosclerosis, which in turn can lead to heart attacks and strokes. life-threatening strokes.
A study involving researchers from the University of California, San Diego examined the relationship between two genes (DNMT3A and TET2), mitochondrial function, inflammation and the formation of atherosclerotic plaques. The results were published in the journal Immunity.
What happens when DNMT3A and TET2 are mutated?
DNMT3A and TET2 refer to a pair of genes that regulate blood cell growth. However, if there is a mutation, the gene pair is associated with an increased risk of developing atherosclerosis, experts report.
"We discovered that the DNMT3A and TET2 genes, in addition to their normal role (...) directly activate the expression of a gene involved in mitochondrial inflammatory pathways, suggesting a new molecular target for atherosclerosis therapies “, explains the author of the study, Dr. Gerald Shadel in a press release.
How do DNMT3A and TET2 mutations lead to atherosclerosis?
When researchers investigated the role of DNMT3A and TET2 mutations in what is known as clonal hematopoiesis, they found that abnormal inflammatory signals associated with DNMT3A and TET2 deficiency in blood cells play an important role in the response inflammation that leads to the development of atherosclerosis. .
However, the question has arisen as to how exactly the DNMT3A and TET2 genes are involved in inflammation and atherosclerosis. "The problem was that we couldn't figure out how DNMT3A and TET2 are involved because the proteins they encode seem to do opposite things in terms of DNA regulation," said study author Dr. Professor Dr. Christophe Verre.
This antagonistic gene activity has led researchers to suspect that other mechanisms may be playing a role. This prompted the team to take a new approach.
Years ago, another research group led by Dr. Shadel discovered the inflammatory pathway now observed when studying mitochondrial DNA stress responses. A unique subset of cellular DNA resides in mitochondria.
The team around Dr. Shadel had studied the effects of mitochondrial DNA stress by deleting a gene (TFAM) that helps mitochondrial DNA to be packaged correctly. The researchers found that by reducing the level of TFAM, mitochondrial DNA was expelled from the mitochondria into the interior of the cell.
This triggers the same molecular alarm signals that warn cells of a bacterial or viral invader and triggers a molecular defense pathway that triggers an inflammatory response, the researchers explain.
Why do mutations cause inflammatory reactions?
In cooperation, the research groups around Professor Dr. Verre and Dr. Shadel now better understand why DNMT3A and TET2 mutations lead to inflammatory responses similar to those observed in mitochondrial DNA stress.
The teams looked at cells from people with normal cells, people with loss-of-function mutations in DNMT3A or TET2 expression, and people with atherosclerosis.
What triggers an increased inflammatory response?
Experimentally reducing the expression of DNMT3A or TET2 in normal blood cells was found to produce similar results to blood cells with loss-of-function mutations and blood cells from people with atherosclerosis. In all three cases, there was an increase in the inflammatory reaction.
How exactly was the inflammation triggered?
Moreover, experts observed that low expression of DNMT3A and TET2 in blood cells leads to reduced expression of TFAM. As a result, abnormal mitochondrial DNA packaging formed, which triggered inflammation due to the released mitochondrial DNA.
What increases plaque formation in atherosclerosis
“We found that the DNMT3A and TET2 mutations impede their ability to bind and activate the TFAM gene. The absence or reduction of this binding activity leads to the release of mitochondrial DNA and an overactive mitochondrial inflammatory response,” explains study author Dr. Isidoro Cobo.
According to the research team, this process can exacerbate plaque formation in atherosclerosis. (as)
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This text corresponds to the specifications of the specialized medical literature, medical guidelines and current studies and has been verified by health professionals.
Sources:Isidoro Cobo, Tiffany N. Tanaka, Kailash Chandra, Mangalhara Addison, Lana Calvin Yeang, et al. : DNA methyltransferase 3 alpha and TET methylcytosine dioxygenase 2 retain mitochondrial DNA-mediated interferon signaling in macrophages; in: Immunity (published 08/04/2022), ImmunityUniversity of California - San Diego: Mitochondrial DNA Mutations Linked to Heart Disease Risk (published 08/04/2022), University of California - San Diego
This article contains general advice only and should not be used for self-diagnosis or treatment. It cannot substitute a visit to the doctor.