MicroRNA-223-3p Protect Against Radiation-Induced Cardiac Toxicity by Alleviating Myocardial Oxidative Stress and Programmed Cell Death via Targeting the AMPK Pathway.

Dao-Ming Zhang,Yong-Fa Zheng,Tian Tang,Jun-Jian Deng,Xi-Ming Xu,Yao-Gui Wu,Lin Xiong

doi:10.3389/fcell.2021.801661

Abstract

Objectives: Radiotherapy improves the survival rate of cancer patients, yet it also involves some inevitable complications. Radiation-induced heart disease (RIHD) is one of the most serious complications, especially the radiotherapy of thoracic tumors, which is characterized by cardiac oxidative stress disorder and programmed cell death. At present, there is no effective treatment strategy for RIHD; in addition, it cannot be reversed when it progresses. This study aims to explore the role and potential mechanism of microRNA-223-3p (miR-223-3p) in RIHD. Methods: Mice were injected with miR-223-3p mimic, inhibitor, or their respective controls in the tail vein and received a single dose of 20 Gy whole-heart irradiation (WHI) for 16 weeks after 3 days to construct a RIHD mouse model. To inhibit adenosine monophosphate activated protein kinase (AMPK) or phosphodiesterase 4D (PDE4D), compound C (CompC) and AAV9-shPDE4D were used. Results: WHI treatment significantly inhibited the expression of miR-223-3p in the hearts; furthermore, the levels of miR-223-3p decreased in a radiation time-dependent manner. miR-223-3p mimic significantly relieved, while miR-223-3p inhibitor aggravated apoptosis, oxidative damage, and cardiac dysfunction in RIHD mice. In addition, we found that miR-223-3p mimic improves WHI-induced myocardial injury by activating AMPK and that the inhibition of AMPK by CompC completely blocks these protective effects of miR-223-3p mimic. Further studies found that miR-223-3p lowers the protein levels of PDE4D and inhibiting PDE4D by AAV9-shPDE4D blocks the WHI-induced myocardial injury mediated by miR-223-3p inhibitor. Conclusion: miR-223-3p ameliorates WHI-induced RIHD through anti-oxidant and anti-programmed cell death mechanisms via activating AMPK by PDE4D regulation. miR-223-3p mimic exhibits potential value in the treatment of RIHD.

Highlights

With the increasing cancer incidence, radiotherapy (RT) has become an important treatment approach
The serum creatine kinase MB isoenzyme (CK-MB) and lactate dehydrogenase (LDH), indicators associated with cardiac injury, were reduced with miR-223-3p mimic treatment (Figure 1D)
The end-diastolic pressure in the left ventricle (LVEDP) of whole-heart irradiation (WHI) mice was restored with miR-223-3p mimic treatment (Figure 1G)

Summary

Introduction

With the increasing cancer incidence, radiotherapy (RT) has become an important treatment approach. Radiation-induced heart disease (RIHD) is one of the most serious complications, which is characterized by oxidative stress and cell loss (Ping et al, 2020). Mediastinal radiation therapy stimulates the atherosclerosis process, resulting in early onset coronary artery disease. Valvular disease caused by RT usually affects the left valve, with aortic regurgitation being the most common. It can lead to aortic stenosis that requires surgical intervention. A number of large clinical studies have confirmed that radiation therapy increases the risk of heart disease-related deaths (Laugaard Lorenzen et al, 2020). It is currently believed that RIHD is the result of the interaction of multiple mechanisms through multiple perturbed pathways; oxidative stress is considered to be the main one of them (Ping et al, 2020)

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