Chemerin is a new sex-specific target in aortic stenosis concomitant with diabetes regulated by the aldosterone/mineralocorticoid receptor axis

Diabetes mellitus (DM) increases the risk of aortic stenosis (AS) and worsens its pathophysiology in a sex-specific manner. Aldosterone/mineralocorticoid receptor (Aldo/MR) pathway participates in early stages of AS and in other diabetic-related cardiovascular complications. We aim to identify new sex-specific Aldo/MR targets in AS complicated with DM. We performed discovery studies using Olink Proteomics® technology in 87 AS patient-derived aortic valves (AVs) (N=28 and N=19 non-diabetic and diabetic men; N=32 and N=8 non-diabetic and diabetic women, respectively) and human cytokine array (N=24 AVs/sex/condition). Both approaches revealed chemerin as a target differentially upregulated in AVs from male diabetic patients, further validated in a cohort of stenotic AVs (N=283, 27.6% DM, 59.4% men). Valvular chemerin levels directly correlated with VIC activation, MR, inflammation, angiogenesis and calcification markers exclusively in diabetic men. In vitro, Aldo (10^-8M) treatment exclusively increased chemerin levels in valve interstitial cells (VICs) from male DM patients. Aldo also upregulated inflammatory, angiogenic and osteogenic markers in DM and non-DM donors’ VICs, which were prevented by MR antagonism. Increased glucose levels in cell media upregulated chemerin in VICs from male diabetic patients. Overall, RARRES2-knockdown in male diabetic VICs resulted in downregulation of inflammatory, angiogenic and osteogenic markers and blocked Aldo-induced responses in high glucose conditions. These data suggest the Aldo/MR pathway selectively increases chemerin in VICs from diabetic men, promoting inflammation, angiogenesis and calcification associated to AS progression.