CIRBP-OGFR axis safeguards against cardiomyocyte apoptosis and cardiotoxicity induced by chemotherapy.

Abstract

Cold-inducible RNA-binding protein (CIRBP) is documented to be required for maintaining cardiac function, however, its role in chemotherapy-induced cardiotoxicity remains obscured. Herein, we report that CIRBP decreases cardiomyocyte apoptosis and attenuates cardiotoxicity through disrupting OGF-OGFR signal. CIRBP deficiency is involved in diverse chemotherapeutic agents induced cardiomyocyte apoptosis. Delivery of exogenous CIRBP to the mouse myocardium significantly mitigated doxorubicin-induced cardiac apoptosis and dysfunction. Specifically, OGFR was identified as a downstream core effector responsible for chemotherapy-induced cardiomyocyte apoptosis. CIRBP was shown to interact with OGFR mRNA and to repress OGFR expression by reducing mRNA stability. CIRBP-mediated cytoprotection against doxorubicin-induced cardiac apoptosis was demonstrated to largely involve OGFR repression by CIRBP. NTX as a potent antagonist of OGFR successfully rescued CIRBP ablation-rendered susceptibility to cardiac dyshomeostasis upon exposure to doxorubicin, whereas another antagonist ALV acting only on opioid receptors did not. Taken together, our results demonstrate that CIRBP confers myocardium resistance to chemotherapy-induced cardiac apoptosis and dysfunction by dampening OGF/OGFR axis, shedding new light on the mechanisms of chemo-induced cardiotoxicity and providing insights into the development of an efficacious cardioprotective strategy for cancer patients.

• Authors: Cihang Liu, Xiaolei Cheng, Junyue Xing, Jun Li, Zhen Li, Dongdong Jian, Ying Wang, Shixing Wang, Ran Li, Wanjun Zhang, Dongxing Shao, Xiaohan Ma, Xiru Chen, Jia Shen, Chao Shi, Zhiping Guo, Wengong Wang, Taibing Fan, Lin Liu, Hao Tang
• Journal: International journal of biological sciences (Int J Biol Sci) Vol. 18 Issue 7 Pg. 2882-2897 ( 2022) ISSN: 1449-2288 [Electronic] Australia
• PMID: 35541895 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• CIRBP protein, human
• Cirbp protein, mouse
• RNA-Binding Proteins
• Enkephalin, Methionine
• Doxorubicin

Topics

• Animals
• Apoptosis (drug effects)
• Cardiotoxicity (etiology, metabolism, pathology)
• Cell Proliferation
• Doxorubicin (toxicity)
• Enkephalin, Methionine (metabolism, pharmacology)
• Humans
• Mice
• Myocytes, Cardiac (drug effects, metabolism)
• RNA-Binding Proteins (genetics)