What does this research mean for the field?

MiR-19b prevents the development of calcific phenotypes in female aortic stenosis by targeting the mineralocorticoid receptor (NR3C2), a pathway that can be therapeutically mitigated with mineralocorticoid receptor antagonists. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

Investigate the effects of miR-19b on mineralocorticoid receptor regulation and calcification in female valve interstitial cells associated with aortic stenosis.

May 16, 2026

MiRNA-19b targets mineralocorticoid receptor and prevents calcification of female valve interstitial cells

Key Points

Investigate the effects of miR-19b on mineralocorticoid receptor regulation and calcification in female valve interstitial cells associated with aortic stenosis.
Analyzed miR-19b levels in serum and aortic valves of patients with severe aortic stenosis and controls (n=293)
Conducted in vitro calcification models using valve interstitial cells from both sexes
Performed rescue experiments with agomiR-19b and MR antagonism to assess effects on calcification and osteoinflammatory markers.
MiR-19b expression was lower in stenotic aortic valves than controls, with higher levels observed in female patients (p=0.0258)
Restoration of miR-19b reduced calcification and mineralocorticoid receptor expression in vitro and ex vivo
MR antagonism in female valve interstitial cells prevented calcification and decreased expression of osteogenic markers.

Abstract

Abstract Background Sex-dependent mechanisms determine clinically relevant phenotypes in aortic stenosis (AS), predominantly calcific and osteoinflammatory in men, and fibrotic in women. Fibrosis is fundamental to pathophysiological bone formation; however, it is unknown why osteogenesis and calcification are not prominent in female AS. Mineralocorticoid receptor (MR/NR2C3) signaling mediates sex-dependent responses in AS, but the underlying regulatory mechanisms have not been specified. miR-19b expression was previously described in human aortic valves. Purpose We aimed to explore the sex-dependent role of miR-19b on calcific AS and MR regulation as well as the potential of drug-repurposing for commercially available MR antagonists. Methods Levels of miR-19b in serum and aortic valves (AVs) were studied in patients with severe AS and controls, along with the expression of in silico predicted targets and osteoinflammatory markers. In vitro experiments including calcification modelling, miR19b rescue and MR antagonism were conducted in valve interstitial cells (VICs) from both sexes. Results MiR-19b was predicted to potentially regulate ‘Aldosterone-regulated sodium reabsorption’ (NR3C2). The expression of miR-19b was studied in AVs and serum samples from patients with severe AS undergoing elective surgical valve replacement (n=293, 60.6% men) and in control donors (autopsies) (n=36, 69.44% men). MiR-19b expression was lower in stenotic AVs than in controls. Moreover, miR-19b was higher and NR3C2 lower in stenotic AVs from women when compared to AVs from men. In women, both the expression of valvular and serum miR-19b was associated with more inflamed and osteogenic AVs. The expression of valvular miR-19b was progressively downregulated in healthyfibroticcalcific areas only in women AVs (p=0.0258). Mechanistic experiments in VICs demonstrated that the basal expression of miR19b was higher in female VICs than in male’s (n≥3/sex), paralleling an inverse expression of NR2C3. Conversely, during calcification miR-19b was downregulated whilst NR2C3 increased, all in line with our clinical observations. Rescue experiments (agomiR-19b), in vitro (VICs) and ex vivo (cultured human explanted AVs), evidenced that miR19b restoration diminished calcification, MR expression and osteoinflammatory cues. MR antagonism protected female VICs against calcification, the expression of osteogenic markers and prevented from the upregulation of miR-19b targets. Conclusions MiR-19b may prevent women from developing calcific phenotypes in AS by targeting NR3C2. Pharmacological MR antagonism alternatively mitigates calcific phenotypes towards by regulating NR3C2. Taken together, these findings open new avenues for the development of drug-repurposing strategies in AS.

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