A study by researchers at Baylor College of Medicine and partner institutions has uncovered a previously unrecognized way blood vessels protect themselves from damage and slow the progression of atherosclerosis. The survey results are Proceedings of the National Academy of Scienceswith implications for both vascular precision medicine and the safety of certain emerging cancer treatments.
Atherosclerosis is a disease in which fatty deposits slowly build up in the arteries, making them narrow and hard over time. This reduces blood flow and doesn’t provide enough oxygen to vital organs, which can lead to a heart attack, stroke, or poor circulation. ”
Dr. Yuqing Huo, Research Corresponding Author, Professor, Danny B. Jones Endowed Chair in Ophthalmology, Baylor College of Medicine
Dr. Huo is a professor of medicine and molecular and cell biology at Baylor University and a member of the Heart and Vascular Institute.
Dr. Huo added, “Atherosclerosis is a leading cause of death despite fat-reducing therapy. Part of the reason is that the non-adipose drivers of vascular damage are poorly defined. In this study, we took a closer look at the endothelial cells that line blood vessels and their response to factors that promote atherosclerosis.”
Atherosclerotic lesions preferentially develop in arterial regions exposed to turbulent flow (d-flow), leading to DNA damage, genomic stress, endothelial damage, and endothelial barrier dysfunction.
“We know that d-flow can reprogram endothelial cell metabolism,” said first author Qian Ma, Ph.D., an ophthalmology postdoctoral fellow in the Huo lab. “We focused on understanding the impact of d-flow on the cell’s ability to repair DNA damage. Specifically, we investigated how d-flow affects the synthesis of purines, compounds required for the construction of new DNA molecules needed for DNA repair.”
Huo, Ma and colleagues conducted the study using the carotid artery of a mouse model and a living model. They showed that d-flow stimulates the expression of genes involved in the synthesis of new purines in endothelial cells, and that this response coincides with endothelial cells involved in repairing damaged DNA.
Deleting an enzyme involved in purine synthesis called attic “This caused endothelial cell death, disruption of endothelial barrier integrity, and accelerated atherosclerosis. Purine supplementation reversed these effects,” said Marr.
“Our findings reveal that while d-flow damages endothelial cells, endothelial cells are not passive bystanders but try to protect themselves by engaging in DNA repair pathways that can maintain endothelial barrier function and slow the progression of atherosclerosis,” Huo said. “This study suggests that future treatments that enhance endothelial DNA repair could complement cholesterol-lowering drugs and reduce the risk of atherosclerosis and subsequent heart disease.”
The study also raises concerns about new cancer drugs currently under investigation that inhibit the synthesis of purines. “Our study suggests that these drugs may have the unintended side effect of preventing endothelial cells from repairing damaged DNA,” Huo said. “Our findings support careful evaluation of the potential of these drugs to compromise endothelial cell integrity.”
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Baylor College of Medicine
