Differential aortic aneurysm formation provoked by chemogenetic oxidative stress

Aortic aneurysms are potentially fatal focal enlargements of the aortic lumen; the disease burden disease is increasing as the human population ages. Pathological oxidative stress is implicated in development of aortic aneurysms. We pursued a chemogenetic approach to create an animal model of aortic aneurysm formation using a transgenic mouse line DAAO-TG^Tie2 that expresses yeast D-amino acid oxidase (DAAO) under control of the endothelial Tie2 promoter. In DAAO-TG^Tie2 mice, DAAO generates the reactive oxygen species hydrogen peroxide (H₂O₂) in endothelial cells only when provided with D-amino acids. When DAAO-TG^Tie2 mice are chronically fed D-alanine, the animals become hypertensive and develop abdominal but not thoracic aortic aneurysms. Generation of H₂O₂ in the endothelium leads to oxidative stress throughout the vascular wall. Proteomic analyses indicate that the oxidant-modulated protein kinase JNK1 is dephosphorylated by the phophoprotein phosphatase DUSP3 in abdominal but not thoracic aorta, causing activation of KLF4-dependent transcriptional pathways that trigger phenotypic switching and aneurysm formation. Pharmacological DUSP3 inhibition completely blocks aneurysm formation caused by chemogenetic oxidative stress. These studies establish that regional differences in oxidant-modulated signaling pathways lead to differential disease progression in discrete vascular beds, and identify DUSP3 as a potential pharmacological target for the treatment of aortic aneurysms.

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