Irradiation-Induced Cardiac Connexin-43 and miR-21 Responses Are Hampered by Treatment with Atorvastatin and Aspirin.

Csilla Viczenczova,Narcis Tribulova,Tamara Egan Benova,Rakesh Kukreja,Chang Yin,Jan Slezak,Barbara Szeiffova Bacova,Branislav Kura

doi:10.3390/ijms19041128

Abstract

Radiation of the chest during cancer therapy is deleterious to the heart, mostly due to oxidative stress and inflammation related injury. A single sub-lethal dose of irradiation has been shown to result in compensatory up-regulation of the myocardial connexin-43 (Cx43), activation of the protein kinase C (PKC) signaling along with the decline of microRNA (miR)-1 and an increase of miR-21 levels in the left ventricle (LV). We investigated whether drugs with antioxidant, anti-inflammatory or vasodilating properties, such as aspirin, atorvastatin, and sildenafil, may affect myocardial response in the LV and right ventricle (RV) following chest irradiation. Adult, male Wistar rats were subjected to a single sub-lethal dose of chest radiation at 25 Gy and treated with aspirin (3 mg/day), atorvastatin (0.25 mg/day), and sildenafil (0.3 mg/day) for six weeks. Cx43, PKCε and PKCδ proteins expression and levels of miR-1 as well as miR-21 were determined in the LV and RV. Results showed that the suppression of miR-1 was associated with an increase of total and phosphorylated forms of Cx43 as well as PKCε expression in the LV while having no effect in the RV post-irradiation as compared to the non-irradiated rats. Treatment with aspirin and atorvastatin prevented an increase in the expression of Cx43 and PKCε without change in the miR-1 levels. Furthermore, treatment with aspirin, atorvastatin, and sildenafil completely prevented an increase of miR-21 in the LV while having partial effect in the RV post irradiation. The increase in pro-apoptotic PKCδ was not affected by any of the used treatment. In conclusion, irradiation and drug-induced changes were less pronounced in the RV as compared to the LV. Treatment with aspirin and atorvastatin interfered with irradiation-induced compensatory changes in myocardial Cx43 protein and miR-21 by preventing their elevation, possibly via amelioration of oxidative stress and inflammation.

Highlights

Cardiovascular injury due to radiation is the most common cause of adverse events among cancer survivors [1,2]
We showed that exposure of rats to a single dose of chest irradiation at 25 Gy caused up-regulation in the expression of Cx43, PKCε, and PKCδ in the left ventricle (LV) following six weeks
Our results suggest that cardiac response to chest irradiation is associated with the up-regulation of myocardial Cx43 connected with the suppression of miR-1 and enhanced PKCε and PKCδ signaling in the LV but not in the right ventricle (RV)

Summary

Introduction

Cardiovascular injury due to radiation is the most common cause of adverse events among cancer survivors [1,2]. Key factors responsible for the establishment of cardiovascular injury, i.e., oxidative stress, inflammation, and epigenetic modifications, have been linked to potential treatments and been recently described [1,2]. Ionizing radiation induces oxidative stress and causes changes in the expression of several microRNAs (miRNA)s, including miR-1 and miR-21. An increase of miR-21 is involved in myocardial hypertrophy [3,4] and fibrosis [5]. An increase in miR-21 has been associated with the up-regulation of the protein kinase C (PKC) δ [6], which is implicated in tissue remodeling. Molecular mechanisms of the irradiation induced injury are unknown and there is currently a lack of treatment strategies

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Methods

Conclusion