- ADAMTS7, which is both a metalloproteinase enzyme and a proteoglycan, is considered a therapeutic target for coronary artery disease, but how it contributes to atherosclerosis has been unclear
- Researchers at Massachusetts General Hospital generated a catalytic mutant form of ADAMTS7 and found in mouse models of atherosclerosis that loss of Adamts7 protease function was equivalent to Adamts7 knockout
- Vascular smooth muscle cells from the Adamts7-mutant mice showed reduced migration similar to knockout cells and those effects correlated with a protective human variant of ADAMTS7
- Inhibiting the catalytic function of ADAMTS7 is a promising therapeutic approach for atherosclerosis
Several genome-wide association studies have demonstrated variants within a gene known as ADAMTS7 that are associated with coronary artery disease (CAD). Genome-wide association studies usually can't pinpoint the directionality of an association, but studies in mice showed complete loss of Adamts7 protects against atherosclerosis, suggesting ADAMTS7 is pro-atherogenic.
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ADAMTS7 is both a metalloproteinase enzyme and a proteoglycan, and which mechanism promotes atherosclerosis has been unclear. In work supported by a collaboration between the Broad Institute and Bayer AG, Patrick T. Ellinor, MD, PhD, director of the Telemachus & Irene Demoulas Family Foundation Center for Cardiac Arrhythmias at the Corrigan Minehan Heart Center at Massachusetts General Hospital, Sekar Kathiresan, MD, of formerly the Center for Genomic Medicine, and colleagues have demonstrated for the first time that the protease activity of ADAMTS7 is essential to its pro-atherogenic effects.
Thus, the catalytic activity domain of ADAMTS7 could be a therapeutic target for curtailing atherosclerosis, according to the team's report in Circulation Research.
In Vitro Experiments
The team first generated a catalytic mutant form of ADAMTS7. In an in vitro cleavage assay, they demonstrated that it had lost its protease activity.
Loss of Function vs. Loss of Protein
The team then generated mice that had a catalytically inactive version of Adamts7 and compared them with mice that had Adamts7 knocked out. In two models of atherosclerosis, loss of Adamts7 function was equivalent to complete loss of the protein.
In humans, ADAMTS7 is known to be involved in the migration of vascular smooth muscle cells in response to vascular injury, which contributes to plaque formation. Vascular smooth muscle cells from the Adamts7-mutant mice showed reduced migration similar to that of cells from knockout mice.
Human ADAMTS7 Variant
The researchers studied a human ADAMTS7 coding variant (rs3825807, also called Ser214Pro) that has been associated with reduced CAD risk. This variant reduced ADAMTS7 secretion and reduced the migration of vascular smooth muscle cells.
These findings suggest that targeting ADAMTS7 catalytic activity is a promising approach to treating atherosclerosis. The results are particularly important because variants in ADAMTS7 have been linked to a high-risk plaque phenotype and an increase in adverse cardiovascular events.
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