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

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.

Oxidative Stress and Epigenetics: miRNA Involvement in Rare Autoimmune Diseases

“…TXNIP can bind and inactivate both Thioredoxin 1 (TRX1) and 2 (TRX2), which play a central role in protecting cells from oxidative stress [ 149 ]. In agreement with this protective role, Ding et al and Zhang et al reported that overexpression of this miRNA resulted in increased levels of Nrf2 by targeting kelch-like ECH-associated protein 1 (Keap1), the principal Nrf2 inhibitor [ 150 , 151 ].…”

Radiation-induced circulating microRNAs linked to echocardiography parameters after radiotherapy

“…Prior studies on radiation-induced toxicity in animal models identified several miRNAs associated with this process through experimental models. Notably, these include miR-223 ( 54 ), miR-21 ( 55 ) and miR-212 ( 56 ). Paper by Zhang et al.…”

miR-223: a key regulator of pulmonary inflammation

“…A recent study also showed that miR-223 mimics could reduce the NLRP3 protein expression level and suppress chronic inflammation in DE ( 89 ). For radiation-induced heart disease (RIHD), miR-223 mimics could improve myocardial injury by activating adenosine monophosphate activated protein kinase (AMPK) ( 192 ). On the other hand, miR-223 inhibitors could cause hyper-activation of NLRP3 in the J774A.1 murine macrophages infected by subsp.…”