Rac1 mediates cadherin-11 induced cellular pathogenic processes in aortic valve calcification.

Background: Calcific aortic valve disease (CAVD), a major cause for surgical aortic valve replacement, currently lacks available pharmacological treatments. Cadherin-11 (Cad11), a promising therapeutic target, promotes aortic valve calcification in vivo, but direct Cad11 inhibition in clinical trials has been unsuccessful. Targeting of downstream Cad11 effectors instead may be clinically useful; however, the downstream effectors that mediate Cad11-induced aortic valve cellular pathogenesis have not been investigated.

Mechanistic insights into volatile anesthetic modulation of K2P channels.

K2P potassium channels are known to be modulated by volatile anesthetic (VA) drugs and play important roles in clinically relevant effects that accompany general anesthesia. Here, we utilize a photoaffinity analog of the VA isoflurane to identify a VA-binding site in the TREK1 K2P channel. The functional importance of the identified site was validated by mutagenesis and biochemical modification.

Induction of aortic valve calcification by celecoxib and its COX-2 independent derivatives is glucocorticoid-dependent.

Background: Celecoxib, a selective cyclooxygenase-2 inhibitor, was recently associated with increased incidence of aortic stenosis and found to produce a valvular calcification risk in vitro. Several cyclooxygenase-2 independent celecoxib derivatives have been developed and identified as possible therapies for inflammatory diseases due to their cadherin-11 inhibitory functions. Potential cardiovascular toxicities associated with these cyclooxygenase-2 independent celecoxib derivatives have not yet been investigated.

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

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.