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

  • Redox Biol. 2022 Feb:49:102219. doi: 10.1016/j.redox.2021.102219.
Mengjie Xiao  1 ,  Yufeng Tang  2 ,  Jie Wang (a)  1 ,  Guangping Lu  1 ,  Jianlou Niu  3 ,  Jie Wang (b)  1 ,  Jiahao Li  1 ,  Qingbo Liu  1 ,  Zhaoyun Wang  4 ,  Zhifeng Huang  3 ,  Yuanfang Guo  1 ,  Ting Gao  1 ,  Xiaohui Zhang  1 ,  Shouwei Yue  5 ,  Junlian Gu  6
Affiliations
  • 1. School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
  • 2. Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, 250014, China.
  • 3. School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
  • 4. Department of Neurosurgical Intensive Care Unit & Emergency Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China.
  • 5. Rehabilitation Center, Qilu Hospital, Cheelo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
  • 6. School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China. Electronic address: [email protected].
PMID: 34990928 DOI: 10.1016/j.redox.2021.102219
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.

Keywords
Adriamycin; Apoptosis; Cardiotoxicity; FGF1 variant; Oxidative stress.
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