Reduced versican cleavage due to Adamts9 haploinsufficiency is associated with cardiac and aortic anomalies

作者：Kern Christine B^*; Wessels Andy; McGarity Jessica; Dixon Laura J; Alston Ebony; Argraves W Scott; Geeting Danielle; Nelson Courtney M; Menick Donald R; Apte Suneel S

来源：Matrix Biology, 2010, 29(4): 304-316.

DOI：10.1016/j.matbio.2010.01.005

• ADAMTS
• Versican
• Extracellular matrix
• Myxomatous valves

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.

• 出版日期2010-5