Abstract
Objective - Calcific aortic valve (AoV) disease is a significant clinical problem for which the regulatory mechanisms are poorly understood. Enhanced cell-cell adhesion is a common mechanism of cellular aggregation, but its role in calcific lesion formation is not known. Cadherin-11 (Cad-11) has been associated with lesion formation in vitro, but its function during adult valve homeostasis and pathogenesis is not known. This study aims to elucidate the specific functions of Cad-11 and its downstream targets, RhoA and Sox9, in extracellular matrix remodeling and AoV calcification. Approach and Results - We conditionally overexpressed Cad-11 in murine heart valves using a novel double-transgenic Nfatc1 Cre;R26-Cad11 TglTg mouse model. These mice developed hemodynamically significant aortic stenosis with prominent calcific lesions in the AoV leaflets. Cad-11 overexpression upregulated downstream targets, RhoA and Sox9, in the valve interstitial cells, causing calcification and extensive pathogenic extracellular matrix remodeling. AoV interstitial cells overexpressing Cad-11 in an osteogenic environment in vitro rapidly form calcific nodules analogous to in vivo lesions. Molecular analyses revealed upregulation of osteoblastic and myofibroblastic markers. Treatment with a Rho-associated protein kinase inhibitor attenuated nodule formation, further supporting that Cad-11-driven calcification acts through the small GTPase RhoA/Rho-associated protein kinase signaling pathway. Conclusions - This study identifies one of the underlying molecular mechanisms of heart valve calcification and demonstrates that overexpression of Cad-11 upregulates RhoA and Sox9 to induce calcification and extracellular matrix remodeling in adult AoV pathogenesis. The findings provide a potential molecular target for clinical treatment.
Original language | English (US) |
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Pages (from-to) | 1627-1637 |
Number of pages | 11 |
Journal | Arteriosclerosis, thrombosis, and vascular biology |
Volume | 36 |
Issue number | 8 |
DOIs | |
State | Published - Aug 1 2016 |
Keywords
- aortic valve
- cadherin
- cell adhesion
- extracellular matrix
- stenosis
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine