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

doi:10.1007/s00109-023-02284-w

. 2023 Mar;101(3):237-248.

doi: 10.1007/s00109-023-02284-w. Epub 2023 Jan 20.

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

Ze Gong^#¹, Jiaqi Huang^#¹, Daidai Wang², Shiyu Yang¹, Zihan Ma¹, Yi Fu¹, Qingbian Ma³, Wei Kong⁴

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.
² Department of Emergency Medicine, Peking University Third Hospital, Beijing, 100191, People's Republic of China.
³ Department of Emergency Medicine, Peking University Third Hospital, Beijing, 100191, People's Republic of China. maqingbian@126.com.
⁴ 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. kongw@bjmu.edu.cn.

^# Contributed equally.

PMID: 36662289
DOI: 10.1007/s00109-023-02284-w

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

Ze Gong et al. J Mol Med (Berl). 2023 Mar.

. 2023 Mar;101(3):237-248.

doi: 10.1007/s00109-023-02284-w. Epub 2023 Jan 20.

Authors

Ze Gong^#¹, Jiaqi Huang^#¹, Daidai Wang², Shiyu Yang¹, Zihan Ma¹, Yi Fu¹, Qingbian Ma³, Wei Kong⁴

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.
² Department of Emergency Medicine, Peking University Third Hospital, Beijing, 100191, People's Republic of China.
³ Department of Emergency Medicine, Peking University Third Hospital, Beijing, 100191, People's Republic of China. maqingbian@126.com.
⁴ 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. kongw@bjmu.edu.cn.

^# Contributed equally.

PMID: 36662289
DOI: 10.1007/s00109-023-02284-w

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.

Keywords: ADAMTS-7; BAPN; Biomarker; Thoracic aortic aneurysm and dissection.

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References

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1. Nienaber CA, Clough RE (2015) Management of acute aortic dissection. Lancet (London, England) 385(9970):800–811. https://doi.org/10.1016/S0140-6736(14)61005-9 - DOI - PubMed
1. Gawinecka J, Schönrath F, von Eckardstein A (2017) Acute aortic dissection: pathogenesis, risk factors and diagnosis. Swiss Med Wkly 147:w14489. https://doi.org/10.4414/smw.2017.14489
1. Ren W, Liu Y, Wang X, Piao C, Ma Y, Qiu S, Jia L, Chen B, Wang Y, Jiang W et al (2018) The complement C3a-C3aR axis promotes development of thoracic aortic dissection via regulation of MMP2 expression. J Immunol (Baltimore, Md. : 1950) 200(5):1829–1838. https://doi.org/10.4049/jimmunol.1601386
1. Sakai LY, Keene DR, Renard M, De Backer J (2016) FBN1: The disease-causing gene for Marfan syndrome and other genetic disorders. Gene 591(1):279–291. https://doi.org/10.1016/j.gene.2016.07.033 - DOI - PubMed

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[1] Goldfinger JZ, Halperin JL, Marin ML, Stewart AS, Eagle KA, Fuster V (2014) Thoracic aortic aneurysm and dissection. J Am Coll Cardiol 64(16):1725–1739. https://doi.org/10.1016/j.jacc.2014.08.025 - DOI - PubMed

[2] Goldfinger JZ, Halperin JL, Marin ML, Stewart AS, Eagle KA, Fuster V (2014) Thoracic aortic aneurysm and dissection. J Am Coll Cardiol 64(16):1725–1739. https://doi.org/10.1016/j.jacc.2014.08.025 - DOI - PubMed

[3] Nienaber CA, Clough RE (2015) Management of acute aortic dissection. Lancet (London, England) 385(9970):800–811. https://doi.org/10.1016/S0140-6736(14)61005-9 - DOI - PubMed

[4] Nienaber CA, Clough RE (2015) Management of acute aortic dissection. Lancet (London, England) 385(9970):800–811. https://doi.org/10.1016/S0140-6736(14)61005-9 - DOI - PubMed

[5] Gawinecka J, Schönrath F, von Eckardstein A (2017) Acute aortic dissection: pathogenesis, risk factors and diagnosis. Swiss Med Wkly 147:w14489. https://doi.org/10.4414/smw.2017.14489

[6] Gawinecka J, Schönrath F, von Eckardstein A (2017) Acute aortic dissection: pathogenesis, risk factors and diagnosis. Swiss Med Wkly 147:w14489. https://doi.org/10.4414/smw.2017.14489

[7] Ren W, Liu Y, Wang X, Piao C, Ma Y, Qiu S, Jia L, Chen B, Wang Y, Jiang W et al (2018) The complement C3a-C3aR axis promotes development of thoracic aortic dissection via regulation of MMP2 expression. J Immunol (Baltimore, Md. : 1950) 200(5):1829–1838. https://doi.org/10.4049/jimmunol.1601386

[8] Ren W, Liu Y, Wang X, Piao C, Ma Y, Qiu S, Jia L, Chen B, Wang Y, Jiang W et al (2018) The complement C3a-C3aR axis promotes development of thoracic aortic dissection via regulation of MMP2 expression. J Immunol (Baltimore, Md. : 1950) 200(5):1829–1838. https://doi.org/10.4049/jimmunol.1601386

[9] Sakai LY, Keene DR, Renard M, De Backer J (2016) FBN1: The disease-causing gene for Marfan syndrome and other genetic disorders. Gene 591(1):279–291. https://doi.org/10.1016/j.gene.2016.07.033 - DOI - PubMed

[10] Sakai LY, Keene DR, Renard M, De Backer J (2016) FBN1: The disease-causing gene for Marfan syndrome and other genetic disorders. Gene 591(1):279–291. https://doi.org/10.1016/j.gene.2016.07.033 - DOI - PubMed

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

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

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