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ADAMTS-7 deficiency attenuates thoracic aortic aneurysm and dissection in mice

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Abstract

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening cardiovascular disease with severe extracellular matrix (ECM) remodeling that lacks efficient early stage diagnosis and nonsurgical therapy. A disintegrin and metalloproteinase with thrombospondin motif 7 (ADAMTS-7) is recognized as a novel locus for human coronary artery atherosclerosis. Previous work by us and others showed that ADAMTS-7 promoted atherosclerosis, postinjury neointima formation, and vascular calcification. However, whether ADAMTS-7 is involved in TAAD pathogenesis is unknown. We aimed to explore the alterations in ADAMTS-7 expression in human and mouse TAAD, and investigate the role of ADAMTS-7 in TAAD formation. A case–control study of TAAD patients (N = 86) and healthy participants (N = 88) was performed. The plasma ADAMTS-7 levels were markedly increased in TAAD patients within 24 h and peaked in 7 days. A TAAD mouse model was induced with 0.5% β-aminopropionitrile (BAPN) in drinking water. ELISA analysis of mouse plasma, Western blotting, and immunohistochemical staining of aorta showed an increase in ADAMTS-7 in the early stage of TAAD. Moreover, ADAMTS-7-deficient mice exhibited significantly attenuated TAAD formation and TAAD rupture-related mortality in both male and female mice, which was accompanied by reduced artery dilation and inhibited elastin degradation. ADAMTS-7 deficiency caused repressed inflammatory response and complement system activation during TAAD formation. An increase in plasma ADAMTS-7 is a novel biomarker for human TAAD. ADAMTS-7 deficiency attenuates BAPN-induced murine TAAD. ADAMTS-7 is a potential novel target for TAAD diagnosis and therapy.

Key messages

  • A case-control study revealed increased plasma ADAMTS-7 is a risk factor for TAAD.

  • ADAMTS-7 was elevated in plasma and aorta at early stage of mouse TAAD.

  • ADAMTS-7 knockout attenuated mouse TAAD formation and mortality in both sexes.

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Acknowledgements

We thank Mr. Hao Liu and Dr. Xueyuan Yang from Peking University for kindly helping collecting clinical records in human study.

Funding

This research was supported by funding from the National Natural Science Foundation of China (NSFC, 81921001, 81730010, 31930056, 82100436 and 82230010), and the National Key R&D Program of China (2019YFA 0801600, 2022YFA 1302900).

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  1. Ze Gong and Jiaqi Huang contributed equally.

Authors and Affiliations

  1. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, People’s Republic of China

    Ze Gong, Jiaqi Huang, Shiyu Yang, Zihan Ma, Yi Fu & Wei Kong

  2. Department of Emergency Medicine, Peking University Third Hospital, Beijing, 100191, People’s Republic of China

    Daidai Wang & Qingbian Ma

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Contributions

All authors contributed to the study conception and design. Human study was designed by Wei Kong and Qingbian Ma and performed by Ze Gong and Daidai Wang. Animal study was designed by Wei Kong, Yi Fu, and Ze Gong. Material preparation, data collection, and analysis were performed by Ze Gong, Jiaqi Huang, Zihan Ma, and Shiyu Yang. The first draft of the manuscript was written by Ze Gong and Jiaqi Huang and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Qingbian Ma or Wei Kong.

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The human case–control study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Peking University Third Hospital (M2020410). Informed consent was obtained from all participants. All animal experiments were performed according to the guidelines of the Institutional Animal Care and Use Committee of Peking University Health Science Center.

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109_2023_2284_MOESM1_ESM.pdf

Supplementary file1 (PDF 1840 KB) Supplementary Figure 1. Ex vivo images of aortas from all eight-group mice. Four groups of 3-week-old mice (BAPN: WT-Male, N=15; TS7KO-Male, N=16; WT-Female, N=17; TS7KO-Female, N=18) were treated with 0.5% BAPN in drinking water for 28 days. And another four groups of 3-week-old mice (CTL: WT-Male, N=6; TS7KO-Male, N=6; WT-Female, N=6; TS7KO-Female, N=6) were fed by normal water as control (one aorta from WT male mice in BAPN group which 19 / 30 died at day 28 failed to collect). For those mice that died from TAAD rupture, death date was marked in red under the image. And Day 28 in orange means those mice with TAAD alive till sacrifice, while Day 28 in black means mice without TAAD. Scale bar = 1 cm, as shown in the image.

109_2023_2284_MOESM2_ESM.pdf

Supplementary file2 (PDF 111 KB) Supplementary Figure 2. ADAMTS-7 knockout inhibited BAPN-induced artery dilation in female mice. (A-D) Two groups of 3-week-old female mice (BAPN: WT, N=17; TS7KO, N=18) were treated with 0.5% BAPN in drinking water for 28 days. And another two groups of 3-week-old female mice (CTL: WT, N=6; TS7KO, N=6) were fed by normal water as control. Maximum diameter of aorta was measured ex vivo at four segments, including ascending aorta (Asc, A), aortic arch (Arch, B), descending aorta (Des, C) and abdominal aorta (Abd, D). *P<0.05 by two-way ANOVA with Sidak’s multiple comparisons test.

109_2023_2284_MOESM3_ESM.pdf

Supplementary file3 (PDF 102 KB) Supplementary Figure 3. Unedited image for western blotting. Edited image and its corresponding unedited image for Figure 2A. Lane samples were described in the image.

Supplementary file4 (DOCX 28 KB)

Supplementary file5 (DOCX 13 KB)

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Gong, Z., Huang, J., Wang, D. et al. ADAMTS-7 deficiency attenuates thoracic aortic aneurysm and dissection in mice. J Mol Med 101, 237–248 (2023). https://doi.org/10.1007/s00109-023-02284-w

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