Coronary Disease Association With ADAMTS7 Is Due to Protease Activity

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 (a disintegrin and metalloproteinase with thrombospondin motifs 7) is protective for atherosclerosis. ADAMTS7 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 2 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, findings consistent with our mouse studies. Conclusions: We demonstrated that loss of ADAMTS7 catalytic function protects against atherosclerosis via phenotype switch of vascular smooth muscle cells 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.

Automated summary

The study found that the catalytic function of ADAMTS7 plays a crucial role in vascular smooth muscle cell migration and atherosclerosis.