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Updated: May 30, 2025
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Published on: March 8, 2019
XOR-Derived ROS in Tie2-Lineage Cells Including Endothelial Cells Promotes Aortic Aneurysm Progression in Marfan
Hiroki Yagi1,2, Hiroshi Akazawa1, Qing Liu1
1Department of Cardiovascular Medicine (H. Yagi, H.A., Q.L., A.S.-K., M.U., H.K., R.M., A.S., S.O., H.T., Norifumi Takeda, I.K.), The University of Tokyo, Bunkyo-ku, Japan.
Background:
Marfan syndrome (MFS) is an inherited disorder caused by mutations in the FBN1 gene encoding fibrillin-1, a matrix component of extracellular microfibrils. The main cause of morbidity and mortality in MFS is thoracic aortic aneurysm and dissection, but the underlying mechanisms remain undetermined.
Methods:
To elucidate the role of endothelial XOR (xanthine oxidoreductase)-derived reactive oxygen species in aortic aneurysm progression, we inhibited in vivo function of XOR either by endothelial cell (EC)-specific disruption of the Xdh gene or by systemic administration of an XOR inhibitor febuxostat in MFS mice harboring the Fbn1 missense mutation p.(Cys1041Gly). We assessed the aberrant activation of mechanosensitive signaling in the ascending aorta of Fbn1C1041G/+ mice. Further analysis of human aortic ECs investigated the mechanisms by which mechanical stress upregulates XOR expression.
Results:
We found a significant increase in reactive oxygen species generation in the ascending aorta of patients with MFS and Fbn1C1041G/+ mice, which was associated with a significant increase in protein expression and enzymatic activity of XOR protein in aortic ECs. Genetic disruption of Xdh in ECs or treatment with febuxostat significantly suppressed aortic aneurysm progression and improved perivascular infiltration of macrophages. Mechanistically, mechanosensitive signaling involving FAK (focal adhesion kinase)-p38 MAPK (p38 mitogen-activated protein kinase) and Egr-1 (early growth response-1) was aberrantly activated in the ascending aorta of Fbn1C1041G/+ mice, and mechanical stress on human aortic ECs upregulated XOR expression through Egr-1 upregulation. Consistently, EC-specific knockout of XOR or systemic administration of febuxostat in Fbn1C1041G/+ mice suppressed reactive oxygen species generation, FAK-p38 MAPK activation, and Egr-1 upregulation.
Conclusions:
Aberrant activation of mechanosensitive signaling in vascular ECs triggered endothelial XOR activation and reactive oxygen species generation, which contributes to the progression of aortic aneurysms in MFS. These findings highlight a drug repositioning approach using a uric acid-lowering drug febuxostat as a potential therapy for MFS.
Insights
In Marfan syndrome, mechanosensitive signaling activates endothelial xanthine oxidoreductase (XOR), increasing reactive oxygen species and driving aortic aneurysm progression. Febuxostat, an XOR inhibitor, shows potential therapeutic benefits for MFS.
Area of Science:
- Cardiovascular Biology
- Genetics and Inherited Diseases
- Molecular Medicine
Background:
- Marfan syndrome (MFS) is an inherited connective tissue disorder caused by FBN1 gene mutations.
- Thoracic aortic aneurysm and dissection are the primary causes of morbidity and mortality in MFS.
- The precise mechanisms underlying aortic aneurysm progression in MFS are not fully understood.
Purpose of the Study:
- To investigate the role of endothelial xanthine oxidoreductase (XOR)-derived reactive oxygen species (ROS) in the progression of aortic aneurysms in Marfan syndrome.
- To explore the therapeutic potential of inhibiting XOR in MFS.
Main Methods:
- Utilized MFS mouse models with an FBN1 missense mutation (p.(Cys1041Gly)) and endothelial cell-specific Xdh gene disruption.
- Administered febuxostat, an XOR inhibitor, systemically to MFS mice.
- Assessed aortic aneurysm progression, mechanosensitive signaling pathways (FAK-p38 MAPK-Egr-1), ROS generation, and macrophage infiltration.
Main Results:
- Elevated ROS generation and increased XOR protein expression/activity were observed in the aortas of MFS patients and mice.
- Inhibition of XOR, either genetically or pharmacologically with febuxostat, significantly reduced aortic aneurysm progression and macrophage infiltration.
- Aberrant activation of FAK-p38 MAPK-Egr-1 mechanosensitive signaling was identified in MFS aortas, with mechanical stress upregulating XOR via Egr-1.
Conclusions:
- Aberrant mechanosensitive signaling in vascular endothelial cells triggers XOR activation and ROS production, contributing to aortic aneurysm development in MFS.
- Febuxostat, a repurposed uric acid-lowering drug, presents a potential therapeutic strategy for Marfan syndrome by targeting endothelial XOR-derived ROS.
