All-trans retinoic acid decreased calcium deposition in human valvular interstitial cells and inhibited calcification of aortic bioprosthetic valves in rat and sheep models.
Does all-trans retinoic acid prevent calcification in preclinical models of aortic valve disease?
Retinoic acid receptor alpha agonists like all-trans retinoic acid represent a potential pharmacological strategy to prevent calcification of native aortic valves and bioprostheses.
BACKGROUND: To date, the only effective treatment of severe aortic stenosis is valve replacement. With the introduction of transcatheter aortic valve replacement and extending indications to younger patients, the use of bioprosthetic valves (BPVs) has considerably increased. The main inconvenience of BPVs is their limited durability because of mechanisms similar as the fibro-calcifying processes observed in native aortic stenosis. One of the major gaps of the field is to identify therapeutic targets to prevent or slow the fibro-calcifying process leading to severe and symptomatic aortic stenosis. METHODS: Explanted valves were collected from patients and organ donor hearts. A comparative transcriptomic analysis was performed on valvular interstitial cells (VIC) obtained from calcified (bicuspid and tricuspid) versus control valves. The mechanisms and consequences of aldehyde dehydrogenase 1 family member A1 (ALDH1A1) downregulation were analyzed in VIC cultures from control human aortic valves. ALDH1A1 was inhibited or silenced and its impact on osteogenic marker expression and calcification processes assessed in VIC. The effect of all-trans retinoic acid on calcification was tested on human VIC cultures and on 2 animal models: the model of subcutaneous implantation of bovine pericardium in rats and the model of xenograft aortic valve replacement in juvenile sheep. RESULTS: as the most downregulated gene in VIC from calcified versus control valves. In human VIC, ALDH1A1 expression is downregulated by TGF-β in a SMAD2/3-dependent manner. ALDH1A1 inhibition promotes an osteoblast-like VIC phenotype and increases calcium deposition through inhibition of retinoic acid receptor alpha signaling. Conversely, VIC treatment with retinoids decreases calcium deposition and attenuates VIC osteoblast activity. Last, all-trans retinoic acid inhibits calcification development of aortic BPV in both in vivo models and improves aortic valve echocardiographic parameters in the xenograft sheep model. CONCLUSIONS: These results show that ALDH1A1 is downregulated in calcified valves, hence promoting VIC transition into an osteoblastic phenotype. Retinoic acid receptor alpha agonists, including all-trans retinoic acid through a drug repositioning strategy, represent a promising and innovative pharmacological approach to prevent calcification of native aortic valves and BPV.
Rosa et al. (2025) studied Aortic valve calcification. All-trans retinoic acid vs. Control was evaluated on Calcification development and calcium deposition. All-trans retinoic acid decreased calcium deposition in human valvular interstitial cells and inhibited calcification of aortic bioprosthetic valves in rat and sheep models.