PALMD regulates aortic valve calcification via altered glycolysis and NF-ΚB-mediated inflammation

Recent genome-wide association and transcriptome-wide association studies have identified an association between the PALMD locus, encoding palmdelphin, a protein involved in myoblast differentiation, and calcific aortic valve disease (CAVD). Nevertheless, the function and underlying mecha-nisms of PALMD in CAVD remain unclear. We herein inves-tigated whether and how PALMD affects the pathogenesis of CAVD using clinical samples from CAVD patients and a hu-man valve interstitial cell (hVIC) in vitro calcification model. We showed that PALMD was upregulated in calcified regions of human aortic valves and calcified hVICs. Furthermore, silencing of PALMD reduced hVIC in vitro calcification, oste-ogenic differentiation, and apoptosis, whereas overexpression of PALMD had the opposite effect. RNA-Seq of PALMD-depleted hVICs revealed that silencing of PALMD reduced glycolysis and nuclear factor-kappa B (NF-kappa B)-mediated inflammation in hVICs and attenuated tumor necrosis factor alpha-induced monocyte adhesion to hVICs. Having established the role of PALMD in hVIC glycolysis, we examined whether glycolysis itself could regulate hVIC osteogenic differentiation and inflammation. Intriguingly, the inhibition of PFKFB3-mediated glycolysis significantly attenuated osteogenic differentiation and inflammation of hVICs. However, silencing of PFKFB3 inhibited PALMD-induced hVIC inflammation, but not oste-ogenic differentiation. Finally, we showed that the over-expression of PALMD enhanced hVIC osteogenic differentiation and inflammation, as opposed to glycolysis, through the activation of NF-kappa B. The present study demon-strates that the genome-wide association- and transcriptome-wide association-identified CAVD risk gene PALMD may promote CAVD development through regulation of glycolysis and NF-kappa B-mediated inflammation. We propose that targeting PALMD-mediated glycolysis may represent a novel therapeutic strategy for treating CAVD.

Automated summary

This study reveals that PALMD, a gene associated with calcific aortic valve disease (CAVD), plays a role in the development of CAVD by regulating glycolysis and NF-kappa B-mediated inflammation. Targeting PALMD-mediated glycolysis may be a novel therapeutic strategy for treating CAVD.