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. Furthermore, the mechanism by which celecoxib produces valvular toxicity is not known. Methods and results: Celecoxib treatment produces a 2.8-fold increase in calcification in ex vivo porcine aortic valve leaflets and a more than 2-fold increase in calcification in porcine aortic valve interstitial cells cultured in osteogenic media. Its cyclooxygenase-2 independent derivative, 2,5-dimethylcelecoxib, produces a similar 2.5-fold increase in calcification in ex vivo leaflets and a 13-fold increase in porcine aortic valve interstitial cells cultured in osteogenic media. We elucidate that this offtarget effect depends on the presence of either of the two media components: dexamethasone, a synthetic glucocorticoid used for osteogenic induction, or cortisol, a natural glucocorticoid present at basal levels in the fetal bovine serum. In the absence of glucocorticoids, these inhibitors effectively reduce calcification. By adding glucocorticoids or hydrocortisone to a serum substitute lacking endogenous glucocorticoids, we show that dimethylcelecoxib conditionally induces a 3.5-fold increase in aortic valve calcification and osteogenic expression. Treatment with the Mitogen-activated protein kinase kinase inhibitor, U0126, rescues the offtarget effect, suggesting that celecoxib and dimethylcelecoxib conditionally augment Mitogen-activated protein kinase kinase/extracellular-signal-regulated kinase activity in the presence of glucocorticoids. Conclusion: Here we identify glucocorticoids as a possible source of the increased valvular calcification risk associated with celecoxib and its cyclooxygenase-2 independent derivatives. In the absence of glucocorticoids, these inhibitors effectively reduce calcification. Furthermore, the offtarget effects are not due to the drug's intrinsic properties as dual cyclooxygenase-2 and cadherin-11 inhibitors. These findings inform future design and development of celecoxib derivatives for potential clinical therapy. (C) 2019 Elsevier Inc. All rights reserved.