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Inflammation is implicated in the pathogenesis of calcific aortic valve disease (CAVD) which is a major contributor to cardiovascular mortality and lacks non-surgical treatment. The progranulin (PGRN) is an important immunomodulatory factor in a variety of inflammatory diseases, including rheumatoid arthritis, osteoarthritis, inflammatory bowel disease and pneumonia. However, its role in calcification of aortic valve remains unknown. We firstly found that PGRN was increased in calcified human aortic valve (AV) tissues. Interestingly, in addition to full-length PGRN (68KD), a much stronger band of approximately 45 KD was also significantly increased. The band of 45 KD (45-GRN), was present in wild type (WT) mouse MEFs and AV but absent in grn−/−MEFs, indicating that it was a specific degradation product derived from PGRN. 45-GRN was upregulated whereas PGRN was reduced in human valve interstitial cells (hVICs) under calcifying conditions which is induced by osteogenic medium (OM). In primary porcine VICs (pVICs), PGRN downregulated TNF-α and α-SMA which was accompanied by downregulation of RUNX2, OPN, OCN, alkaline phosphatase activity and calcium deposition, effects pointing to reduced inflammation, myofibroblastic and osteoblastic transition under calcifying conditions. We overexpressed a mimic of 45-GRN which contains p-G-F-B-A-C in pVICs. However, 45-GRN overexpression promoted OM-induced calcification through activating the Smad1/5/8, NF-κB and AKT signaling pathways. Inhibition of the three signaling pathways suppressed 45-GRN's effect on VICs phenotype transition. 45-GRN promoted TNF-α and expressed converse pathogenic signatures with PGRN during TNF-α stimulation. Collectively, this study provides new insight into the pathogenesis of CAVD, indicating that PGRN is a stratagem in mitigating valve fibrosis/osteoblastic differentiation, and also presenting 45-GRN as a potential target for the treatment of CAVD. Unlabelled Image • The short 45-GRN and full-length PGRN are increased in aortic valve of CAVD. • The short 45-GRN promotes myofibroblastic and osteoblastic transition whereas PGRN inhibits that in VIC. • The short 45-GRN increases the expression of TNF-α in VIC which acts pro-inflammatory. • The short 45-GRN may promote VICs calcification through activating Smad1/5/8, NF-κB and AKT signal pathways. [ABSTRACT FROM AUTHOR]