Differential aortic aneurysm formation provoked by chemogenetic oxidative stress
Apabrita Ayan Das, … , Taylor A. Covington, Thomas Michel
Apabrita Ayan Das, … , Taylor A. Covington, Thomas Michel
Published March 18, 2025
Citation Information: J Clin Invest. 2025;135(9):e188743. https://doi.org/10.1172/JCI188743.
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Research Article Cardiology Vascular biology

Differential aortic aneurysm formation provoked by chemogenetic oxidative stress

Abstract

Aortic aneurysms are potentially fatal focal enlargements of the aortic lumen; the disease burden is increasing as the human population ages. Pathological oxidative stress is implicated in the development of aortic aneurysms. We pursued a chemogenetic approach to create an animal model of aortic aneurysm formation using a transgenic mouse line, DAAO-TGTie2, that expresses yeast d-amino acid oxidase (DAAO) under control of the endothelial Tie2 promoter. In DAAO-TGTie2 mice, DAAO generated the ROS hydrogen peroxide (H2O2) in endothelial cells only when provided with d-amino acids. When DAAO-TGTie2 mice were chronically fed d-alanine, the animals became hypertensive and developed abdominal, but not thoracic, aortic aneurysms. Generation of H2O2 in the endothelium led to oxidative stress throughout the vascular wall. Proteomics analyses indicated that the oxidant-modulated protein kinase JNK1 was dephosphorylated by the phosphoprotein phosphatase DUSP3 (dual specificity phosphatase 3) in abdominal, but not thoracic, aorta, causing activation of Kruppel-like Factor 4 (KLF4)-dependent transcriptional pathways that triggered phenotypic switching and aneurysm formation. Pharmacological DUSP3 inhibition completely blocked the 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.

Authors

Apabrita Ayan Das, Markus Waldeck-Weiermair, Shambhu Yadav, Fotios Spyropoulos, Arvind Pandey, Tanoy Dutta, Taylor A. Covington, Thomas Michel

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Figure 5

Quantitative proteomics analyses of abdominal aorta in d-alanine–treated DAAO-TGTie2 and control mice.

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Quantitative proteomics analyses of abdominal aorta in d-alanine–treated...
(A) The JNK1 protein network and connecting targets identified using quantitative proteomics (27) to compare abdominal aorta in d-alanine–treated DAAO-TGTie2 transgenic and control mice. Node sizes were assigned according to the Eigen factor values, and the colors assigned according to the degree centrality (blue signifies highest centrality and red indicates lowest centrality). Edges are unweighted, but the distance between 2 nodes is assigned according to their closeness centrality values. (B and C) Gradient plots of the same data as shown in A. B shows selected MAPK cascade proteins along the abscissa, with the degree centrality of specific nodes quantitated along the ordinate. C is based on the same data as in B, but analyzed for Eigen factor centrality for selected MAPK cascade proteins, as shown on the ordinate. (D) Lollipop plot presenting the GO biological processes identified from the same set of proteins used to create A. The abscissa presents the enrichment score that corresponds to the enriched biological process listed on the ordinate. Color of the bubbles represents the number of genes identified in each process, and size of the bubbles represents the –log2Padj values, as noted in the lookup table shown to the left of the plot. Data in this figure are based on the results of at least 3 independent experiments.