Potential role of full-length and nonfull-length progranulin in affecting aortic valve calcification.

Abstract

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.

• Authors: Gaigai Huang, Liqin An, Mengtian Fan, Menghao Zhang, Bin Chen, Mengying Zhu, Jinghong Wu, Yan Liu, Yue Wang, Qin Huang, Qiong Shi, Yaguang Weng
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 141 Pg. 93-104 (04 2020) ISSN: 1095-8584 [Electronic] England
• PMID: 32247641 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• Culture Media
• NF-kappa B
• Progranulins
• Smad Proteins
• Tumor Necrosis Factor-alpha
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Aortic Valve (drug effects, metabolism, pathology)
• Aortic Valve Stenosis (metabolism)
• Apoptosis (drug effects)
• Calcinosis (metabolism)
• Cell Differentiation (drug effects)
• Culture Media (pharmacology)
• Female
• Humans
• Male
• Mice
• Mice, Knockout
• Middle Aged
• Myofibroblasts (drug effects, metabolism, pathology)
• NF-kappa B (metabolism)
• Osteoblasts (drug effects, metabolism)
• Osteogenesis (drug effects)
• Phenotype
• Progranulins (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Smad Proteins (metabolism)
• Tumor Necrosis Factor-alpha (pharmacology)