Differential aortic aneurysm formation provoked by chemogenetic oxidative stress
Apabrita Ayan Das, Markus Waldeck-Weiermair, Shambhu Yadav, Fotios Spyropoulos, Arvind Pandey, Tanoy Dutta, Taylor A. Covington, Thomas Michel
Apabrita Ayan Das, Markus Waldeck-Weiermair, Shambhu Yadav, Fotios Spyropoulos, Arvind Pandey, Tanoy Dutta, Taylor A. Covington, Thomas Michel
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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 1

Effects of chemogenetic oxidative stress on mortality and vascular pathology in DAAO-TGTie2 transgenic mice.

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Effects of chemogenetic oxidative stress on mortality and vascular patho...
(A and B) Kaplan-Meier survival curves for DAAO-TGTie2 and control mice exposed to chemogenetic oxidative stress. (A) Survival curve for d-alanine–fed DAAO-TGTie2 transgenic mice (blue line), with their wild-type d-alanine–fed littermates serving as negative (genetic) controls (orange line). (B) Treatment control in which DAAO-TGTie2 transgenic mice were fed either d-alanine (blue line) or l-alanine (orange line). Chronic d-alanine–fed DAAO-TGTie2 transgenic mice show drastically reduced survival compared either with their d-alanine–fed wild-type control littermates (P < 0.001 by ANOVA) or with l-alanine–fed transgenic littermates (P < 0.001). (C) Results of systolic blood pressure measurements in DAAO-TGTie2 transgenic (blue line) and their wild-type littermates (orange line) following the initiation of d-alanine feeding; there is no change in blood pressure until 8 weeks of age, at which point blood pressure increases significantly (**P < 0.01, ***P < 0.001, ANOVA). (D and E) Measurements of aortic diameter (determined by sonography) in d-alanine–fed DAAO-TGTie2 transgenic mice (blue line) and their wild-type littermates (orange line) are shown for the abdominal aorta (D) (***P < 0.001) and the thoracic aorta (E). In the DAAO-TGTie2 transgenic mice, abdominal (P < 0.001) but not thoracic aortae increase in size following chronic d-alanine feeding. (F) Time course plotting the change in systolic blood pressure and the change in abdominal aorta dimensions following the initiation of d-alanine feeding in DAAO-TGTie2 transgenic animals compared with wild-type littermate controls; changes in blood pressure and abdominal aortic dimension followed similar time courses. All measurements were made by observers blinded to genotype and treatment. All mice were on a similar C57BL/6 genetic background. Data are presented as means ± SEM of at least 3 independent experiments.