Reduced versican cleavage due to Adamts9 haploinsufficiency is associated with cardiac and aortic anomalies |
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Authors: | Christine B Kern Andy Wessels Jessica McGarity Laura J Dixon Ebony Alston W Scott Argraves Danielle Geeting Courtney M Nelson Donald R Menick Suneel S Apte |
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Institution: | 1. Department of Regenerative Medicine and Cell Biology, 171 Ashley Avenue, Medical University of South Carolina, Charleston, SC 29425, USA;2. Department of Biomedical Engineering, Lerner Research Institute ND-20, Cleveland Clinic, 9500 Euclid Avenue, Cleveland OH 44195, USA;3. Department of Medicine Division of Cardiology, Room 201 114 Doughty Street, Medical University of South Carolina, Charleston, SC 29425, USA |
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Abstract: | Here, we demonstrate that ADAMTS9, a highly conserved versican-degrading protease, is required for correct cardiovascular development and adult homeostasis. Analysis of Adamts9+/LacZ adult mice revealed anomalies in the aortic wall, valvulosinus and valve leaflets. Abnormal myocardial projections and ‘spongy’ myocardium consistent with non-compaction of the left ventricle were also found in Adamts9+/LacZ mice. During development, Adamts9 was expressed in derivatives of the Secondary Heart Field, vascular smooth muscle cells in the arterial wall, mesenchymal cells of the valves, and non-myocardial cells of the ventricles, but expression also continued in the adult heart and ascending aorta. Thus, the adult cardiovascular anomalies found in Adamts9+/LacZ hearts could result from subtle developmental alterations in extracellular matrix remodeling or defects in adult homeostasis. The valvular and aortic anomalies of Adamts9+/LacZ hearts were associated with accumulation of versican and a decrease in cleaved versican relative to WT littermates. These data suggest a potentially important role for ADAMTS9 cleavage of versican, or other, as yet undefined substrates in development and allostasis of cardiovascular extracellular matrix. In addition, these studies identify ADAMTS9 as a potential candidate gene for congenital cardiac anomalies. Mouse models of ADAMTS9 deficiency may be useful to study myxomatous valve degeneration. |
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