COX-2 Is Downregulated in Human Stenotic Aortic Valves and Its Inhibition Promotes Dystrophic Calcification

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.

The Complex Interplay of Inflammation, Metabolism, Epigenetics, and Sex in Calcific Disease of the Aortic Valve

“…In fact, inhibition of the enzyme by celecoxib, along with genetic depletion in the Klotho deficient mice (a known model of valve calcification) reduced calcification of the valve and of animal-derived VICs in vitro (32). On the other hand, a word of caution about the therapeutic potential of COX-2 inhibition by the celecoxib has been also raised by other studies, showing that in human VICs from stenotic valves treatment with the drug may increase the so-called dystrophic calcification, a process mediated by TGF-β1 and related to VICs myofibroblast differentiation and apoptosis (27,(33)(34)(35)(36). Early histological studies on 347 surgically excised aortic valves showed that 83% of them presented dystrophic calcifications, while lamellar bone with active bone remodeling were observed in only 13% (37).…”

Cardiac Calcifications: Phenotypes, Mechanisms, Clinical and Prognostic Implications

“…The resident cells are also different: vascular smooth muscle cells (VSMCs) for the vessels and valve interstitial cells (VICs), essentially fibroblasts, for the valve. These are the cells that, under pathologic conditions, may undergo myofibrogenic [4], osteogenic, and even chondrogenic differentiation [5].…”

Adding a “Notch” to Cardiovascular Disease Therapeutics: A MicroRNA-Based Approach

“…Aortic valve stenosis is currently the most common valvular heart disease, and to date, there are no effective therapies to prevent or slow down the progression of this pathology ( Minamino-Muta et al, 2017 ). Alteration of functions of ECs, SMCs, and valve interstitial cells (VICs), which form the aortic valve, all contribute to its calcification ( Rutkovskiy et al, 2017 ; van der Ven et al, 2017 ; Vieceli Dalla Sega et al, 2020 ).…”