Role of ADAMTS-5 in Aortic Dilatation and Extracellular Matrix Remodeling

Fava, Marika; Barallobre-Barreiro, Javier; Mayr, Ursula; Lu, Ruifang; Didangelos, Athanasios; Baig, Ferheen; Lynch, Magnus; Catibog, Norman; Joshi, Abhishek; Barwari, Temo; Yin, Xiaoke; Jahangiri, Marjan; Mayr, Manuel

doi:10.1161/atvbaha.117.310562

Cited by 69 publications

(68 citation statements)

References 51 publications

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“…Fava et al also reported that LRP1 was profoundly reduced in aortas of mice lacking the catalytic domain of ADAMTS-5. Moreover, silencing LRP1 in SMCs also reduced the expression of ADAMTS-5 and attenuated ADAMTS-5-mediated versican cleavage (42). Based on these reports, we speculate that LRP1 plays an important role in the biological effects of ADAMTS-5.…”

Section: Discussionsupporting

confidence: 54%

ADAMTS-5 Decreases in Aortas and Plasma From Aortic Dissection Patients and Alleviates Angiotensin II-Induced Smooth Muscle-Cell Apoptosis

Zeng

Gan

Liu

et al. 2020

Front. Cardiovasc. Med.

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Background: Acute aortic dissection (AAD) is associated with degeneration of the aortic media and accompanied by vascular extracellular matrix (ECM) remodeling. Recently, a disintegrin and metalloproteinase with thrombospondin type 1 motifs-5 (ADAMTS-5) has been reported to be involved in ECM remodeling and vascular diseases. The aim of this study was to examine ADAMTS-5 levels in AAD patients and investigate the underlying mechanisms. Methods: Aortic tissue samples were collected from normal donors and AAD patients, and the expression of ADAMTS-5 was analyzed in all aortic tissues. In addition, plasma levels of ADAMTS-5, matrix metalloproteinase (MMP)-2 and MMP-9, and tumor necrosis factor-α (TNF-α) were measured in repeated samples from AAD patients and compared to the non-AAD (NAD) group. In addition, we investigated the effects of ADAMTS-5 in smooth muscle cell (SMC) apoptosis. Results: The results showed that ADAMTS-5 expression was significantly reduced in the aortas of AAD patients and that SMCs were the main source of ADAMTS-5. In addition, the plasma ADAMTS-5 level was lower, but plasma MMP-2, MMP-9, and TNF-α levels were increased in the AAD patients. Multivariate linear regression analyses showed that a decreased ADAMTS-5 level in patients was independently associated with an increased risk of AAD. Furthermore, recombinant human ADAMTS-5 significantly ameliorated angiotensin (Ang II)-evoked SMC apoptosis. Conclusions: ADAMTS-5 shows promise as a novel potential biomarker for AAD, and regulation of SMC is a possible mechanism for the effects of ADAMTS-5.

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Section: Discussionsupporting

confidence: 54%

ADAMTS-5 Decreases in Aortas and Plasma From Aortic Dissection Patients and Alleviates Angiotensin II-Induced Smooth Muscle-Cell Apoptosis

Zeng

Gan

Liu

et al. 2020

Front. Cardiovasc. Med.

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“…16,18 Several studies conducted in mouse models of aortic dilation have recently reported that ADAMTS/L family members play a role in aortopathies, and their effects are often detected or enhanced by angiotensin II infusion. [19][20][21] Members of this family would be interesting candidate genes in hTAAD. Our genetic approach links ADAMTSL6 to hTAAD.…”

Section: Introductionmentioning

confidence: 99%

Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm

Elbitar

Renard

Arnaud

et al. 2021

Genetics in Medicine

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Purpose: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease with often unrecognized inherited forms. We sought to identify novel pathogenic variants associated with autosomal dominant inheritance of TAAD. Methods: We analyzed exome sequencing data from 35 French TAAD families and performed next-generation sequencing capture panel of genes in 1114 unrelated TAAD patients. Functional effects of pathogenic variants identified were validated in cell, tissue, and mouse models. Results: We identified five functional variants in THSD4 of which two heterozygous variants lead to a premature termination codon. THSD4 encodes ADAMTSL6 (member of the ADAMTS/L superfamily), a microfibril-associated protein that promotes fibrillin-1 matrix assembly. The THSD4 variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils. Thsd4 +/mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying a THSD4 variant and from Thsd4 +/mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix. Conclusion: These findings highlight the role of ADAMTSL6 in aortic physiology and TAAD pathogenesis. They will improve TAAD management and help develop new targeted therapies.

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“…In this issue of ATVB , Fava et al 8 extend their previous work implicating versican accumulation in models of mechanical and lipid-induced vascular injury. Although ADAMTS1-4 and 5 have been linked to aortic aneurysms, only ADAMTS5 was preferentially expressed in the ascending aorta in the mouse model.…”

mentioning

confidence: 73%

Insights Into the Role of Regional Proteoglycan Metabolism in Thoracic Aortic Aneurysms

Brasier

2018

ATVB

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Role of ADAMTS-5 in Aortic Dilatation and Extracellular Matrix Remodeling

Abstract: Supplemental Digital Content is available in the text.

Cited by 69 publications

References 51 publications

ADAMTS-5 Decreases in Aortas and Plasma From Aortic Dissection Patients and Alleviates Angiotensin II-Induced Smooth Muscle-Cell Apoptosis

ADAMTS-5 Decreases in Aortas and Plasma From Aortic Dissection Patients and Alleviates Angiotensin II-Induced Smooth Muscle-Cell Apoptosis

Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm

Insights Into the Role of Regional Proteoglycan Metabolism in Thoracic Aortic Aneurysms

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