Cytoprotective Effects of Dinitrosyl Iron Complexes on Viability of Human Fibroblasts and Cardiomyocytes.

Natalia Pavlovna Akentieva,Stanislav Ivanovich Shram,Artur Rasimovich Gizatullin,Nikolai Zhelev,Natalia Ivanovna Shkondina,Natalia Alekseevna Sanina,Sergei Michailovich Aldoshin,Tatyana Romanovna Prikhodchenko

doi:10.3389/fphar.2019.01277

Abstract

Nitric oxide (NO) is an important signaling molecule that plays a key role in maintaining vascular homeostasis. Dinitrosyl iron complexes (DNICs) generating NO are widely used to treat cardiovascular diseases. However, the involvement of DNICs in the metabolic processes of the cell, their protective properties in doxorubicin-induced toxicity remain to be clarified. Here, we found that novel class of mononuclear DNICs with functional sulfur-containing ligands enhanced the cell viability of human lung fibroblasts and rat cardiomyocytes. Moreover, DNICs demonstrated remarkable protection against doxorubicin-induced toxicity in fibroblasts and in rat cardiomyocytes (H9c2 cells). Data revealed that the DNICs compounds modulate the mitochondria function by decreasing the mitochondrial membrane potential (ΔΨm). Results of flow cytometry showed that DNICs were not affected the proliferation, growth of fibroblasts. In addition, this study showed that DNICs did not affect glutathione levels and the formation of reactive oxygen species in cells. Moreover, results indicated that DNICs maintained the ATP equilibrium in cells. Taken together, these findings show that DNICs have protective properties in vitro. It was further suggested that DNICs may be uncouplers of oxidative phosphorylation in mitochondria and protective mechanism is mainly provided by the leakage of excess charge through the mitochondrial membrane. It is assumed that the DNICs have the therapeutic potential for treating cardiovascular diseases and for decreasing of chemotherapy-induced cardiotoxicity in cancer survivors.

Highlights

Cardiovascular disease (CVD) is the leading cause of death worldwide
It was shown that these Dinitrosyl iron complexes (DNICs) are effective Nitric oxide (NO) donors and have more than twice high NO-generating ability compared to the commercial NO-donor diethylenetriamine (Figures 2–4, Supplementary Material) (Sanina et al, 2014; Sanina et al, 2015)
It was shown that when DNIC#6 was dissolved in an aqueous solution, 16 nmol NO was released for 50 s, after 100 s the NO level dropped to 12 nmol and remained constant for 500 s

Summary

Introduction

Cardiovascular disease (CVD) is the leading cause of death worldwide. According to the World Health Organization (WHO), CVD are in first place in terms of mortality in the world (WHO newsletter, 2015). In addition other toxic effects include myocardial ischemia, systolic or diastolic myocardial dysfunction, cardiomyopathy, chronic heart failure, arterial or pulmonary hypertension, strokes, pericarditis, arrhythmias, thromboembolic disease, and others, extremely adversely affecting the prognosis of these patients (Łacko et al, 2002; Adão et al, 2013; Truong et al, 2014). Cardiomyopathy caused by chemotherapy for cancer was mainly due to the use of cumulative doses of anthracyclines (doxorubicin, epirubicinum), and trastuzumab, which are the chemotherapeutic agents with the most pronounced cardiac side effects (Łacko et al, 2002; Adão et al, 2013; Truong et al, 2014; Zaorsky et al, 2017; Carrillo-Larco and Bernabe-Ortiz, 2018; Fidale et al, 2018; Ng et al, 2018)

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