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

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.

• Authors: Ze Gong, Jiaqi Huang, Daidai Wang, Shiyu Yang, Zihan Ma, Yi Fu, Qingbian Ma, Wei Kong
• Journal: Journal of molecular medicine (Berlin, Germany) (J Mol Med (Berl)) Vol. 101 Issue 3 Pg. 237-248 (03 2023) ISSN: 1432-1440 [Electronic] Germany
• PMID: 36662289 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Chemical References

• 1,3,4,6-tetra-O-acetyl-2-azido-2-deoxyglucopyranose
• Aminopropionitrile
• ADAMTS7 protein, human
• Adamts7 protein, mouse

Topics

• Animals
• Female
• Humans
• Male
• Mice
• Aminopropionitrile (adverse effects, metabolism)
• Aorta (metabolism)
• Aorta, Thoracic (metabolism, pathology)
• Aortic Aneurysm, Thoracic (chemically induced, metabolism)
• Aortic Dissection (etiology)
• Case-Control Studies
• Disease Models, Animal