XOR-Derived ROS in Tie2-Lineage Cells Including Endothelial Cells Promotes Aortic Aneurysm Progression in Marfan Syndrome.

BACKGROUND

Marfan syndrome (MFS) is an inherited disorder caused by mutations in the 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 gene or by systemic administration of an XOR inhibitor febuxostat in MFS mice harboring the missense mutation p.(Cys1041Gly). We assessed the aberrant activation of mechanosensitive signaling in the ascending aorta of 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 mice, which was associated with a significant increase in protein expression and enzymatic activity of XOR protein in aortic ECs. Genetic disruption of 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 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 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.