Cadherin-11 Overexpression Induces Extracellular Matrix Remodeling and Calcification in Mature Aortic Valves

Derek C. Sung, Caitlin J. Bowen, Kiran A. Vaidya, Jingjing Zhou, Nikita Chapurin, Andrew Recknagel, Bin Zhou, Jonathan Chen, Michael Kotlikoff, Jonathan T. Butcher

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18 Scopus citations

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 languageEnglish (US)
Pages (from-to)1627-1637
Number of pages11
JournalArteriosclerosis, thrombosis, and vascular biology
Volume36
Issue number8
DOIs
StatePublished - Aug 1 2016

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Keywords

  • aortic valve
  • cadherin
  • cell adhesion
  • extracellular matrix
  • stenosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Sung, D. C., Bowen, C. J., Vaidya, K. A., Zhou, J., Chapurin, N., Recknagel, A., Zhou, B., Chen, J., Kotlikoff, M., & Butcher, J. T. (2016). Cadherin-11 Overexpression Induces Extracellular Matrix Remodeling and Calcification in Mature Aortic Valves. Arteriosclerosis, thrombosis, and vascular biology, 36(8), 1627-1637. https://doi.org/10.1161/ATVBAHA.116.307812