Purine Metabolic Adaptation Protects the Endothelium From Disturbed Flow-Induced DNA Damage and Atherosclerosis

Authors

• Qian Ma
• Yongfeng Cai
• Zhidan Zhang
• Dingwei Zhao
• Yuan Zhao
• Peishan Xu
• Tammy Lu
• Wendy Zhang
• Qiuhua Yang
• Yaqi Zhou
• Varadarajan Sudhahar
• Tohru Fukai
• Hanjoong Jo
• Yiming Xu
• Yuqing Huo

Language

English

Publication Date

5-5-2026

Journal

Proceedings of the National Academy of Sciences of the United States of America

DOI

10.1073/pnas.2526299123

PMID

42060719

PMCID

PMC13142911

PubMedCentral® Posted Date

4-30-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Despite effective lipid-lowering therapies, atherosclerosis continues to be a leading cause of death, with considerable residual cardiovascular risk. Atherosclerotic lesions develop preferentially at arterial regions exposed to disturbed flow (d-flow), which induces genomic stress, endothelial injury, and barrier dysfunction. Hemodynamic forces are known to reprogram endothelial metabolism, but the role of de novo purine synthesis (DNPS), which supplies nucleotides for genome maintenance and whose terminal steps are catalyzed by the bifunctional enzyme ATIC, remains undefined in atherosclerosis. By integrating bulk and single-cell multiomics with in vitro flow systems and in vivo models, we show that d-flow upregulates DNPS and ATIC genes in vitro and in vivo, in concert with a DNA damage/repair state. Endothelial-specific Atic deletion exacerbates DNA damage, apoptosis, barrier dysfunction, and accelerates atherogenesis, while purine-base supplementation rescues repair defects. We further identify MYC as a mechanosensitive driver of ATIC induction. These findings establish a d-flow-MYC-ATIC-DNPS axis that sustains nucleotide sufficiency for DNA repair and maintains endothelial barrier integrity, suggesting potential endothelial-targeted therapeutic strategies for atherosclerosis.

Keywords

DNA Damage, Animals, Atherosclerosis, Purines, Endothelium, Vascular, Mice, Humans, DNA Repair, ATIC, de novo purine synthesis, DNA damage, endothelial cells

Published Open-Access

yes

Recommended Citation

Ma, Qian; Cai, Yongfeng; Zhang, Zhidan; et al., "Purine Metabolic Adaptation Protects the Endothelium From Disturbed Flow-Induced DNA Damage and Atherosclerosis" (2026). Faculty, Staff and Students Publications. 7383.
https://digitalcommons.library.tmc.edu/baylor_docs/7383