COX-2 Is Downregulated in Human Stenotic Aortic Valves and Its Inhibition Promotes Dystrophic Calcification |
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Authors: | Francesco Vieceli Dalla Sega Francesca Fortini Paolo Cimaglia Luisa Marracino Elisabetta Tonet Antonio Antonucci Marco Moscarelli Gianluca Campo Paola Rizzo Roberto Ferrari |
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Affiliation: | 1.Maria Cecilia Hospital, GVM Care & Research, 48033 Cotignola, Italy; (F.V.D.S.); (F.F.); (P.C.); (M.M.); (R.F.);2.Laboratory for Technologies of Advanced Therapies (LTTA), Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy;3.Cardiovascular Institute, Azienda Ospedaliero-Universitaria di Ferrara, 44124 Cona, Italy; (E.T.); (A.A.); (G.C.) |
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Abstract: | Calcific aortic valve disease (CAVD) is the result of maladaptive fibrocalcific processes leading to a progressive thickening and stiffening of aortic valve (AV) leaflets. CAVD is the most common cause of aortic stenosis (AS). At present, there is no effective pharmacotherapy in reducing CAVD progression; when CAVD becomes symptomatic it can only be treated with valve replacement. Inflammation has a key role in AV pathological remodeling; hence, anti-inflammatory therapy has been proposed as a strategy to prevent CAVD. Cyclooxygenase 2 (COX-2) is a key mediator of the inflammation and it is the target of widely used anti-inflammatory drugs. COX-2-inhibitor celecoxib was initially shown to reduce AV calcification in a murine model. However, in contrast to these findings, a recent retrospective clinical analysis found an association between AS and celecoxib use. In the present study, we investigated whether variations in COX-2 expression levels in human AVs may be linked to CAVD. We extracted total RNA from surgically explanted AVs from patients without CAVD or with CAVD. We found that COX-2 mRNA was higher in non-calcific AVs compared to calcific AVs (0.013 ± 0.002 vs. 0.006 ± 0.0004; p < 0.0001). Moreover, we isolated human aortic valve interstitial cells (AVICs) from AVs and found that COX-2 expression is decreased in AVICs from calcific valves compared to AVICs from non-calcific AVs. Furthermore, we observed that COX-2 inhibition with celecoxib induces AVICs trans-differentiation towards a myofibroblast phenotype, and increases the levels of TGF-β-induced apoptosis, both processes able to promote the formation of calcific nodules. We conclude that reduced COX-2 expression is a characteristic of human AVICs prone to calcification and that COX-2 inhibition may promote aortic valve calcification. Our findings support the notion that celecoxib may facilitate CAVD progression. |
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Keywords: | CAVD (calcific aortic valve disease) AS (aortic stenosis) COX-2 (cyclooxygenase-2) AVICs (aortic valve interstitial cells) celecoxib calcific nodules calcification aortic valve calcification |
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