Celecoxib Is Associated With Dystrophic Calcification and Aortic Valve Stenosis

Abstract

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Off Target But on Track to New Strategies to Mitigate Calcific Aortic Valve Disease

“…Thus, the investigative team examined porcine aortic VIC-mediated matrix calcification in the presence of celecoxib or dimethyl celecoxib—the latter a methylated congener that also binds CDH11 but does not inhibit cyclooxygenase 2 (Cox2). To the authors’ surprise, celcoxib increased, whereas dimethyl celecoxib inhibited, calcified nodule formation in VICs grown under prosclerotic conditions (e.g., transforming growth factor–beta with biaxial mechanical strain) (3). Furthermore, celecoxib increased the contractile myofibroblast phenotype of VICs in this relevant culture model.…”

“…Comparison was made to other nonsteroidal anti-inflammatory drugs such as naproxen or ibuprofen that do not bind CDH11. In the adjusted retrospective analysis, celecoxib use was associated with a significant 25% increase in AS risk, whereas no such association was found with naproxen or ibuprofen exposure (3). Thus, celecoxib use emerges as a plausible risk factor for calcific AS, potentially related to mechanisms involving VIC Cox2 inhibition in the setting of CDH11 modulation (3).…”

“…Why is this paper from Bowler et al. (3) so significant? There are several important features, but 2 stand out as very helpful to consider, including their implications.…”

“…In this issue of JACC: Basic to Translational Science , Bowler et al. (3) have innovatively followed through on a chemoinformatic clue that pointed to previously unknown polypharmacology. A prior independent, mass spectrometry–based study recently identified the widely used nonsteroidal anti-inflammatory drug celecoxib as a high-affinity ligand for cadherin 11 (CDH11), also known as osteoblast cadherin (4).…”

“…Importantly, aortic valve endothelial cells exhibited little to no procalcific activity or modulation. To further establish the relationship between celecoxib and calcific aortic valve disease (CAVD), the authors queried the Vanderbilt Synthetic Derivative, a powerful de-identified patient database enabling an analysis of celecoxib use and the risk for calcific aortic stenosis (AS) (3). Comparison was made to other nonsteroidal anti-inflammatory drugs such as naproxen or ibuprofen that do not bind CDH11.…”