A new FGF1 variant protects against adriamycin-induced cardiotoxicity via modulating p53 activity.

Abstract

A cumulative and progressively developing cardiomyopathy induced by adriamycin (ADR)-based chemotherapy is a major obstacle for its clinical application. However, there is a lack of safe and effective method to protect against ADR-induced cardiotoxicity. Here, we found that mRNA and protein levels of FGF1 were decreased in ADR-treated mice, primary cardiomyocytes and H9c2 cells, suggesting the potential effect of FGF1 to protect against ADR-induced cardiotoxicity. Then, we showed that treatment with a FGF1 variant (FGF1ΔHBS) with reduced proliferative potency significantly prevented ADR-induced cardiac dysfunction as well as ADR-associated cardiac inflammation, fibrosis, and hypertrophy. The mechanistic study revealed that apoptosis and oxidative stress, the two vital pathological factors in ADR-induced cardiotoxicity, were largely alleviated by FGF1ΔHBS treatment. Furthermore, the inhibitory effects of FGF1ΔHBS on ADR-induced apoptosis and oxidative stress were regulated by decreasing p53 activity through upregulation of Sirt1-mediated p53 deacetylation and enhancement of murine double minute 2 (MDM2)-mediated p53 ubiquitination. Upregulation of p53 expression or cardiac specific-Sirt1 knockout (Sirt1-CKO) almost completely abolished FGF1ΔHBS-induced protective effects in cardiomyocytes. Based on these findings, we suggest that FGF1ΔHBS may be a potential therapeutic agent against ADR-induced cardiotoxicity.

• Authors: Mengjie Xiao, Yufeng Tang, Jie Wang (a), Guangping Lu, Jianlou Niu, Jie Wang (b), Jiahao Li, Qingbo Liu, Zhaoyun Wang, Zhifeng Huang, Yuanfang Guo, Ting Gao, Xiaohui Zhang, Shouwei Yue, Junlian Gu
• Journal: Redox biology (Redox Biol) Vol. 49 Pg. 102219 (02 2022) ISSN: 2213-2317 [Electronic] Netherlands
• PMID: 34990928 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Tumor Suppressor Protein p53
• Fibroblast Growth Factor 1
• Doxorubicin

Topics

• Animals
• Apoptosis
• Cardiotoxicity (pathology)
• Doxorubicin (adverse effects)
• Fibroblast Growth Factor 1 (genetics, metabolism, pharmacology)
• Mice
• Myocytes, Cardiac (metabolism)
• Oxidative Stress
• Tumor Suppressor Protein p53 (genetics, metabolism)