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

Siying Wang, Hongjiao Yu, Jun Gao, Jiaxin Chen, Pengcheng He, Hui Zhong, Xiao Tan, Katherine A Staines, Vicky E Macrae, Xiaodong Fu, Lei Jiang, Dongxing Zhu

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Recent genome-wide association (GWAS) and transcriptome-wide association (TWAS) 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 mechanisms of PALMD in CAVD remain unclear. In this study, we investigated whether and how PALMD affects the pathogenesis of CAVD using clinical samples from CAVD patients and a human 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, osteogenic differentiation, and apoptosis, whereas overexpression of PALMD had the opposite effect. RNA sequencing of PALMD-depleted hVICs revealed that silencing of PALMD reduced glycolysis and nuclear factor-κB (NF-κB)-mediated inflammation in hVICs, and attenuated tumor necrosis factor α (TNFα)-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 osteogenic differentiation. Finally, we showed that the overexpression of PALMD enhanced hVIC osteogenic differentiation and inflammation, as opposed to glycolysis, through the activation of NF-κB. The present study demonstrates that the GWAS and TWAS-identified CAVD risk gene PALMD may promote CAVD development through regulation of glycolysis and NF-κB-mediated inflammation. We propose that targeting PALMD-mediated glycolysis may represent a novel therapeutic strategy for treating CAVD. [Abstract copyright: Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.]
Original languageEnglish
Article number101887
Number of pages14
JournalJournal of Biological Chemistry
Issue number5
Publication statusPublished - 1 Apr 2022

Bibliographical note

Funding Information:
Funding and additional information—This study was supported by funding from the National Natural Science Foundation of China (No. 82170428, 81800428 to D. Z.), The ‘Yangcheng Scholar’ Grant of Guangzhou (No. 202032768 to D. Z.), Guangdong Natural Science Foundation (No. 2018A030310178 to D. Z.), and Science and Technology Projects of Guangzhou (No. 201904010289 to D. Z.). L. J. is supported by the National Natural Science Foundation of China (No. 81800262) and Science and Technology Planning Project of Guangzhou (No. 201903010005). P. H. is supported by Natural Science Foundation of Guangdong Province (No. 2021A1515011121).

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  • glycolysis
  • Cardiovascular disease
  • Calcification
  • Calcific aortic valve disease
  • NF-kappa B
  • human valve interstitial cells
  • inflammation


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