Cadherin-11 Loss Prevents Contraction in Aortic Valve Interstitial Cells

Motivation: Calcific aortic valve disease affects 25% of the Western population over 65 and is currently treated by valve replacement. Alternative therapies remain scarce, likely because the mechanism of calcification is... [ view full abstract ]

Motivation: Calcific aortic valve disease affects 25% of the Western population over 65 and is currently treated by valve replacement. Alternative therapies remain scarce, likely because the mechanism of calcification is largely unknown. Dystrophic calcification is initiated by TGF-β-mediated myofibroblastic differentiation of resident aortic valve interstitial cells (AVICs), which exhibit increased contractility and a subsequent imbalance of intercellular tension that lead to apoptosis. Cadherin-11 (CDH11), a mechanosensitive transmembrane protein involved in cell-cell adhesion, is responsible for mediating this tension. Both CDH11 and α-smooth muscle actin (αSMA), a myofibroblast marker involved in cell contractility, are overexpressed in diseased human valves.

Methods: WT, CDH11+/-, and CDH11-/- AVICs isolated from immorto-mice were evaluated via western blot and immunofluorescence for protein expression, qPCR for transcription, and collagen gel assay for contraction. WT AVICs were infected with mCherry-tagged CDH11 as an overexpression model. WT and CDH11-/- AVICs were subjected to 10% cyclic biaxial strain for 24h before qPCR.

Results and Discussion: Loss of CDH11 resulted in reduced TGF-β1-mediated contraction (A). Surprisingly, this loss in contractility was inversely related to αSMA expression (B). Increases in catenin expression (B) indicate dramatic changes in intracellular cadherin signaling. Interestingly, strain induces an increase in RhoA transcription only in the presence of CDH11, and CDH11 loss reduces myosin light chain II expression (C). Thus, loss of CDH11 may prevent contraction by either preventing linkage between contractile AVICs or by reducing production of contractile machinery. These results indicate that CDH11 may be a promising therapeutic target for calcific aortic valve disease.