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

Redox Biology

Zhifeng Huang¹  Zhaoyun Wang²  Yufeng Tang³  Junlian Gu⁴  Shouwei Yue⁵  Ting Gao⁵  Xiaohui Zhang⁵  Guangping Lu⁵  Jiahao Li⁵  Qingbo Liu⁵  Mengjie Xiao⁵  Jie Wang, (b)⁵  Jie Wang, (a)⁵  Jianlou Niu⁶  Yuanfang Guo⁶ 

[1] Emergency Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China;;Department of Neurosurgical Intensive Care Unit &Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, 250014, China;Rehabilitation Center, Qilu Hospital, Cheelo College of Medicine, Shandong University, Jinan, Shandong, 250012, China;School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China;School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China;

关键词: Adriamycin;    Cardiotoxicity;    FGF1 variant;    Oxidative stress;    Apoptosis;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown