Researchers have identified a new gene-activation pathway caused by lipids associated with coronary artery disease, in a study published in Nature Communications.
The discovery that exposure to lipids activates a gene called MTHFD2 in the walls of blood vessels was made using a computational model in the human heart.
Atherosclerosis is caused by the buildup of a complex mixture of components, commonly referred to as plaque, within the inner lining of arteries. Oxidized phospholipids (oxPAPC) are abundant in this arterial plaque and are thought to promote atherosclerosis progression. However, the specific cellular processes caused by these lipids on the arterial surface are still not well understood. The cells composing the inner surface of blood vessels, called endothelial cells, are at the forefront of the atherosclerotic process and therefore are a major focus of research into coronary artery disease.
"Endothelial cell response to lipids has been studied extensively over the years, but it was still unknown that MTHFD2 was even functional in these cells," said co-senior author of the study. The international research team predicted and validated in follow-up experiments that the MTHFD2 gene plays a key role in endothelial cell response to oxidized phospholipids. They found that MTHFD2 was also activated in endothelial cells in response to other factors, such as inflammation or a change in amino acid concentration. This underscores the many factors involved in the development of atherosclerosis that must be understood and taken into consideration when approaching disease therapies.
"Our study showed that when the MTHFD2 gene is activated in endothelial cells in response to oxidized lipids, it sends out molecular 'danger signals' promoting inflammation and stimulating the atherosclerotic process," said another author. "These findings suggest that MTHFD2 could be a novel target to disrupt development and progression of atherosclerosis."
The MTHFD2-controlled cluster redirects metabolism to glycine synthesis to replenish purine nucleotides. Since endothelial cells secrete purines in response to oxPAPC, the MTHFD2-controlled response maintains endothelial ATP. Accordingly, MTHFD2-dependent glycine synthesis is a prerequisite for angiogenesis. Thus, authors propose that endothelial cells undergo MTHFD2-mediated reprogramming toward serine-glycine and mitochondrial one-carbon metabolism to compensate for the loss of ATP in response to oxPAPC during atherosclerosis.
While the role of MTHFD2 in the vascular system was unknown before this study, the gene is known to be consistently activated in cancer, making it a promising target for cancer therapies. MTHFD2 inhibitors are already in clinical trials as anti-cancer therapies. "It's possible that these therapies could also help prevent coronary artery disease, but more research into the specific role of MTHFD2 in atherosclerosis is needed first before proposing it as a target for potential therapy," said the co-senior author.
Gene in artery wall activated by lipids associated with coronary artery disease identified!
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