Abstract 49: Knockout of ADAMTS7, a Novel Human CAD Locus, Reduces Atherosclerosis in Both LDLR and APOE Hyperlipidemic Mouse Models
Multiple genome-wide association studies demonstrate that the genomic locus containing the gene ADAMTS7 is associated with coronary artery disease in humans. ADAMTS7 was not linked to cardiovascular disease prior to those genetic studies, and to date this association has not been validated in experimental models of atherosclerosis. An Adamts7 (Ats7) knockout mouse, with knock-in of a β-galactosidase reporter gene, was bred onto both the LDLR and APOE KO hyperlipidemic mouse models. Atherosclerosis studies were performed on the resultant Ats7/LDLR and Ats7/APOE double KO (dKO) mice and control littermates. Mice were fed western diet for 16 weeks (LDLR) or 10 weeks (APOE), and aortas and aortic roots were harvested for lesion area quantification. In addition, brachiocephalic arteries were dissected for immunohistochemical analysis of lesion composition. No differences in plasma lipids were observed between experimental groups in either study. Ats7/LDLR dKO males (N=7) and females (N=13) displayed significant reductions in lesion formation in aortas by en face (58%, p<0.005 and 61%, p<0.0001 respectively) and in aortic roots (31%, p=0.04 and 22%, p=0.002 respectively) compared to control LDLR -/- male (N=6) and female (N=10) littermates. Additionally, Ats7/APOE dKO males (N=16) and females (N=13) displayed significantly reduced lesion formation by en face (62%, p<0.0001 and 54%, p<0.0001 respectively), and trends towards reduced lesion area in aortic roots (18%, p=0.15 and 22%, p=0.10 respectively) compared to control APOE -/- males (N=9) and females (N=10). Femoral wire injury experiments suggested reduced neointimal formation in Ats7 KO mice at 28 days post-injury, and X-gal staining at multiple timepoints showed adventitial Ats7 expression peaking at 7 days post-injury. Preliminary studies suggest that aortic rings from Ats7/LDLR dKO mice embedded in collagen have reduced cell migration compared to control LDLR aortic rings. In summary, these data represent the first in vivo experimental validation of Adamts7 as a gene involved in atherogenesis, likely through modulation of vascular cell migration into atherosclerotic lesions. These data support the concept that pharmacological inhibition of ADAMTS7 should be atheroprotective in humans.
Author Disclosures: R.C. Bauer: None. J. Tohyama: None. J. Cui: None. X. Zhang: None. C. Yu: None. K. Ou: None. M.S. Parmacek: None. D.J. Rader: None. M.P. Reilly: None.
- © 2014 by American Heart Association, Inc.