Association between ADAMTS7 polymorphism and carotid artery plaque vulnerability

Li, Haowen; Shen, Mowei; Gao, Peiyi; Li, Zi-rui; Cao, Jingli; Zhang, Wenli; Sui, Binbin; Wang, Yuxin; Wang, Yajie

doi:10.1097/md.0000000000017438

Cited by 10 publications

(12 citation statements)

References 24 publications

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“…Thus, our results are in keeping with prior reports that this variant is likely to explain at least a portion of the CAD associated risk at this locus. [6][7][8][9][10] Before ADAMTS7 was reported as CAD genomewide association studies locus, it was demonstrated that ADAMTS7 knockdown prevented, while ADAMTS7 overexpression increased, neointima formation in a rat carotid artery vascular injury model. 12 Mouse knockout studies confirmed that total loss of function reduced neointima formation in the carotid 13 and femoral arteries.…”

Section: Discussionmentioning

confidence: 99%

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Coronary Disease Association With ADAMTS7 Is Due to Protease Activity

Mizoguchi

MacDonald

Bhandary

et al. 2021

Circulation Research

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Rationale: Despite contemporary therapy, coronary artery disease (CAD) remains a leading cause of mortality. Genetic variants at ADAMTS7 have been associated with CAD and the loss of ADAMTS7 is protective for atherosclerosis. ADAMTS7 (a disintegrin and metalloproteinase with thrombospondin motifs 7) is a secreted metalloproteinase and complex proteoglycan, yet the mechanism linking ADAMTS7 to CAD risk remains unresolved. Objective: To investigate the role of ADAMTS7 catalytic function in vascular smooth muscle cellular migration and during atherosclerosis. Methods and Results: We established a new purification strategy for full-length mouse ADAMTS7 and demonstrated the loss of activity in the catalytic mutant form of ADAMTS7. To test if the enzymatic activity of ADAMTS7 mediates atherosclerosis, we generated a catalytically inactive mutant mouse allele and compared it to the Adamts7 knockout. Using two models of atherosclerosis, we found that reducing either ADAMTS7 dosage or catalytic function decreased the burden of atherosclerosis. We demonstrate impaired vascular smooth muscle migration in both Adamts7 catalytic mutant and null cells using a lateral migration wound healing assay. Expression of the wild-type allele rescued the migration phenotype in Adamts7 null cells while expression of the catalytic mutant protein did not. We then characterized a human ADAMTS7 coding variant rs3825807 (Ser214Pro) associated with reduced CAD risk. This variant had a hypomorphic effect on ADAMTS7 secretion and migration of vascular smooth muscle cells (VSMC), findings consistent with our mouse studies. Conclusions: We demonstrated that loss of ADAMTS7 catalytic function protects against atherosclerosis via phenotype switch of VSMCs and that the atherosclerosis protective effects could be mediated by a loss-of-function coding variant associated with CAD risk. In aggregate, we provide compelling evidence that dosage of ADAMTS7 and catalytic function are responsible for the atherosclerotic phenotype, suggesting that the catalytic domain would be an attractive therapeutic target for CAD.

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Section: Discussionmentioning

confidence: 99%

“…Thus, our results are in keeping with prior reports that this variant is likely to explain at least a portion of the CAD associated risk at this locus. 6–10…”

Section: Discussionmentioning

confidence: 99%

Coronary Disease Association With ADAMTS7 Is Due to Protease Activity

Mizoguchi

MacDonald

Bhandary

et al. 2021

Circulation Research

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“…[ 36 ] A recent report stated that the ADAMTS7 variants rs3825807 and rs7173743 were related to the risk of carotid plaque vulnerability. [ 17 ]…”

Section: Discussionmentioning

confidence: 99%

Profile of genetic variations in severely calcified carotid plaques by whole-exome sequencing

Katano

Nishikawa

Yamada

et al. 2020

Surgical Neurology International

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Background: The precise mechanisms of carotid calcification and its clinical significance have not been established. Methods: We classified ten plaques from carotid endarterectomy patients into high- and low-calcified plaques based on the Agatston calcium scores. We performed whole-exome sequencing for genetic profiles with single nucleotide variations (SNVs), insertions, and deletions. Bioinformatic data mining was then conducted to disclose specific gene variations to either high- or low-calcified carotid plaques. Results: In the carotid plaques, G:C>A:T/C:G>T:A transitions as SNVs, insT after C/insC after A as insertions, and delA after G/delT after C as deletions were most frequently observed, but no significant difference was observed between the high- and low-calcified plaque groups in their proportion of base-pair substitution types. In the bioinformatic analysis, SNVs of ATP binding cassette subfamily C member 6 (ADCC6) were more commonly found in high-calcified plaques and SNVs of KLKB1 were more commonly found in low-calcified plaques compared to the other group. No new genetic variants related to calcification or atherosclerosis among those not registered in dbSNP was detected. Conclusion: Our findings clarified the features of base-pair substitutions in carotid plaques, showing no relation to calcification. However, genetic variants in ADCC6 relating to vascular calcification for high-calcified plaques, and in KLKB1 encoding kallikrein associated with vascular regulation of atherosclerosis for low-calcified plaques were more specifically extracted. These results contribute to a better understanding of the genetic basis of molecular activity and calcium formation in carotid plaques.

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“…The Ser214 risk variant was shown to increase prodomain processing and maturation, correlating with an increase in COMP (Cartilage oligomeric matrix protein) degradation and vascular smooth muscle cell migration (4). Additionally, the Ser214 risk allele was associated with an unstable atherosclerotic plaque phenotype and an increase in secondary cardiac events (5)(6)(7)(8). Mouse knockout studies have shown that Adamts7 loss-offunction significantly reduces vascular smooth muscle cell mediated neointimal formation in arterial wire injury models (9,10).…”

Section: Introductionmentioning

confidence: 99%

TAILS identifies candidate substrates and biomarkers of ADAMTS7, a therapeutic protease target in coronary artery disease

MacDonald

Keshishian

Mundorff

et al. 2021

Preprint

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Loss-of-function mutations in the secreted enzyme ADAMTS7 (a disintegrin and metalloproteinase with thrombospondin motifs 7) are associated with protection for coronary artery disease (CAD). ADAMTS7 catalytic inhibition has been proposed as a therapeutic strategy for treating CAD; however, the lack of an endogenous substrate has hindered the development of activity-based biomarkers. To identify ADAMTS7 extracellular substrates and their cleavage sites relevant to vascular disease, we used TAILS (terminal amine isotopic labeling of substrates), a method for identifying protease-generated neo-N termini. We compared the secreted proteome of vascular smooth muscle and endothelial cells expressing either full-length mouse ADAMTS7 WT, catalytic mutant ADAMTS7 E373Q or a control luciferase adenovirus. Significantly enriched N-terminal cleavage sites in ADAMTS7 WT samples were compared to the negative control conditions and filtered for stringency, resulting in catalogs of high confidence candidate ADAMTS7 cleavage sites from our three independent TAILS experiments. Within the overlap of these discovery sets, we identified 24 unique cleavage sites from 16 protein substrates, including cleavage sites in EFEMP1 (EGF-containing fibulin-like extracellular matrix protein 1/Fibulin-3). The ADAMTS7 TAILS preference for EMEMP1 cleavage at the amino acids 123.124 over the adjacent 124.125 site was validated using both endogenous EFEMP1 and purified EFEMP1 in a binary in vitro cleavage assay. Collectively our TAILS discovery experiments have uncovered hundreds of potential substrates and cleavage sites to explore disease related biological substrates and facilitate activity-based ADAMTS7 biomarker development.

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Association between ADAMTS7 polymorphism and carotid artery plaque vulnerability

Cited by 10 publications

References 24 publications

Coronary Disease Association With ADAMTS7 Is Due to Protease Activity

Coronary Disease Association With ADAMTS7 Is Due to Protease Activity

Profile of genetic variations in severely calcified carotid plaques by whole-exome sequencing

TAILS identifies candidate substrates and biomarkers of ADAMTS7, a therapeutic protease target in coronary artery disease

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