Abstract 15199: Knockout of the Coronary Artery Disease Risk Gene Adamts-7 Inhibits Neointima Formation and Stenosis of Arteries
Introduction: The gene encoding the extracellular matrix metalloproteinase ADAMTS-7 displayed genomewide significant association with coronary artery disease (CAD). Remarkably, the risk allele appears to trigger coronary stenosis formation rather than plaque rupture or myocardial infarction. Thus far the functional role of ADAMTS-7 has been studied only in the context of rheumatoid arthritis. The pathomechanism involving ADAMTS-7 in atherosclerosis remains elusive.
Hypothesis: We assessed the hypothesis, that the CAD-risk gene ADAMTS-7 contributes to atherosclerosis by formation of neointima secondary to vascular injury.
Methods: Knockout-mice were generated by insertion of a neomycin cassette and an internal ribosome entry site followed by the beta-Gal-gene. The transgene and knockout were proven by PCR, RT-PCR and detection of beta-galactosidase-activity in X-gal staining. Neointima formation was induced using extravascular ligation of the left common carotid artery in WT- and KO-mice (n=3 per group). The right common carotid artery was treated as a sham control. 10 days after ligation, mice were sacrificed and analyzed by histological staining of the carotid arteries.
Results: Adamts-7-knockout-Mice were vital and appeared normal in growth and behaviour. Using PCR and RT-PCR, the Adamts-7 gene was found to be interrupted by the neomycin cassette and the beta-Gal sequence. X-gal staining demonstrated the correct insertion of the beta-Gal sequence and its expression under the influence of the endogenous Adamts-7-promoter. Adamts-7-knockout-mice did not develop proliferation of intima cells after carotid artery ligation, whereas wildtype-mice showed marked formation of a neointima due to the stimulus. Current studies focus on the elucidation of downstream signaling pathways and pharmacological inhibition of ADAMTS-7 to reveal its potential as a drug target in cardiovascular disease.
Conclusion: We conclude that the extracellular matrix proteinase ADAMTS-7 is pivotal for developing intimal hyperplasia due to vascular injury. Neointima formation may lead to the formation of stenotic lesions therefore promoting coronary artery disease. ADAMTS-7 may be a target for preventive treatment of patients at risk for CAD.
- © 2011 by American Heart Association, Inc.