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

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.

Role of GSH and Iron-Sulfur Glutaredoxins in Iron Metabolism—Review

“…For example, cysteinyl residues in serum albumin can modulate and prolong the vasodilating activity of glutathionyl-DINICs [ 152 ]. It is noteworthy that these DINICs do not seem to affect the cellular glutathione levels, nor cellular proliferation [ 167 ]. They are not toxic to HeLa cells [ 168 ] and they increase the viability of fibroblasts and rat caridiomyocytes [ 167 , 169 ].…”

“…It is noteworthy that these DINICs do not seem to affect the cellular glutathione levels, nor cellular proliferation [ 167 ]. They are not toxic to HeLa cells [ 168 ] and they increase the viability of fibroblasts and rat caridiomyocytes [ 167 , 169 ]. Glutathionyl-DINICs were also reported to accelerate skin wound healing, to inhibit apoptosis, and to suppress endometriosis [ 9 , 170 ].…”

Albumin as a prospective carrier of the nitrosyl iron complex with thiourea and thiosulfate ligands under aerobic conditions

“…31 The in vitro study of complex 1 shows that it increases the viability of fibroblasts by about 8 times compared to control cells not treated with 1 . 32 In addition, complex 1 is an effective cytoprotective agent (survival of fibroblasts increases 2–3 times in its presence) with a duration of about 30 hours, which protects cells from the toxic effect of doxorubicin. 32 It should be noted that hybrid 1 is a much more effective cytoprotective agent than the DNIC of composition [Fe(SC(NH 2 ) 2 ) 2 (NO) 2 ] 2 ·Cl(ClO 4 ), containing only the dinitrosyl cation as the NO donor.…”

“…32 In addition, complex 1 is an effective cytoprotective agent (survival of fibroblasts increases 2–3 times in its presence) with a duration of about 30 hours, which protects cells from the toxic effect of doxorubicin. 32 It should be noted that hybrid 1 is a much more effective cytoprotective agent than the DNIC of composition [Fe(SC(NH 2 ) 2 ) 2 (NO) 2 ] 2 ·Cl(ClO 4 ), containing only the dinitrosyl cation as the NO donor. 32 Therefore, complex 1 is more promising for the treatment of cardiovascular diseases and the reduction of chemotherapy-induced cardiotoxicity in cancer survivors.…”

“…32 It should be noted that hybrid 1 is a much more effective cytoprotective agent than the DNIC of composition [Fe(SC(NH 2 ) 2 ) 2 (NO) 2 ] 2 ·Cl(ClO 4 ), containing only the dinitrosyl cation as the NO donor. 32 Therefore, complex 1 is more promising for the treatment of cardiovascular diseases and the reduction of chemotherapy-induced cardiotoxicity in cancer survivors.…”