Different Antioxidant Efficacy of Two MnII-Containing Superoxide Anion Scavengers on Hypoxia/Reoxygenation-Exposed Cardiac Muscle Cells

Abstract Oxidative stress due to excess superoxide anion ($${{\bf{O}}}_{{\bf{2}}}^{{\boldsymbol{\cdot }}{\boldsymbol{-}}}$$ O2⋅− ) produced by dysfunctional mitochondria is a key pathogenic event of aging and ischemia-reperfusion diseases. Here, a new $${{\bf{O}}}_{{\bf{2}}}^{{\boldsymbol{\cdot }}{\...

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Autores principales:	Matteo Becatti, Andrea Bencini, Silvia Nistri, Luca Conti, Maria Giulia Fabbrini, Laura Lucarini, Veronica Ghini, Mirko Severi, Claudia Fiorillo, Claudia Giorgi, Lorenzo Sorace, Barbara Valtancoli, Daniele Bani
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/04182cdca23f47ec9e1ab153252d5613
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spelling	oai:doaj.org-article:04182cdca23f47ec9e1ab153252d56132021-12-02T15:07:55ZDifferent Antioxidant Efficacy of Two MnII-Containing Superoxide Anion Scavengers on Hypoxia/Reoxygenation-Exposed Cardiac Muscle Cells10.1038/s41598-019-46476-22045-2322https://doaj.org/article/04182cdca23f47ec9e1ab153252d56132019-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-46476-2https://doaj.org/toc/2045-2322Abstract Oxidative stress due to excess superoxide anion ($${{\bf{O}}}_{{\bf{2}}}^{{\boldsymbol{\cdot }}{\boldsymbol{-}}}$$ O2⋅− ) produced by dysfunctional mitochondria is a key pathogenic event of aging and ischemia-reperfusion diseases. Here, a new $${{\bf{O}}}_{{\bf{2}}}^{{\boldsymbol{\cdot }}{\boldsymbol{-}}}$$ O2⋅− -scavenging MnII complex with a new polyamino-polycarboxylate macrocycle (4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diacetate) containing 2 quinoline units (MnQ2), designed to improve complex stability and cell permeability, was compared to parental MnII complex with methyls replacing quinolines (MnM2). MnQ2 was more stable than MnM2 (log K = 19.56(8) vs. 14.73(2) for the equilibrium Mn2+ + L2−, where L = Q2 and M2) due to the involvement of quinoline in metal binding and to the hydrophobic features of the ligand which improve metal desolvation upon complexation. As oxidative stress model, H9c2 rat cardiomyoblasts were subjected to hypoxia-reoxygenation. MnQ2 and MnM2 (10 μmol L−1) were added at reoxygenation for 1 or 2 h. The more lipophilic MnQ2 showed more rapid cell and mitochondrial penetration than MnM2. Both MnQ2 and MnM2 abated endogenous ROS and mitochondrial $${{\bf{O}}}_{{\bf{2}}}^{{\boldsymbol{\cdot }}{\boldsymbol{-}}}$$ O2⋅− , decreased cell lipid peroxidation, reduced mitochondrial dysfunction, in terms of efficiency of the respiratory chain and preservation of membrane potential (Δψ) and permeability, decreased the activation of pro-apoptotic caspases 9 and 3, and increased cell viability. Of note, MnQ2 was more effective than MnM2 to exert cytoprotective anti-oxidant effects in the short term. Compounds with redox-inert ZnII replacing the functional MnII were ineffective. This study provides clues which further our understanding of the structure-activity relationships of MnII-chelates and suggests that MnII-polyamino-polycarboxylate macrocycles could be developed as new anti-oxidant drugs.Matteo BecattiAndrea BenciniSilvia NistriLuca ContiMaria Giulia FabbriniLaura LucariniVeronica GhiniMirko SeveriClaudia FiorilloClaudia GiorgiLorenzo SoraceBarbara ValtancoliDaniele BaniNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-20 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Matteo Becatti Andrea Bencini Silvia Nistri Luca Conti Maria Giulia Fabbrini Laura Lucarini Veronica Ghini Mirko Severi Claudia Fiorillo Claudia Giorgi Lorenzo Sorace Barbara Valtancoli Daniele Bani Different Antioxidant Efficacy of Two MnII-Containing Superoxide Anion Scavengers on Hypoxia/Reoxygenation-Exposed Cardiac Muscle Cells
description	Abstract Oxidative stress due to excess superoxide anion ($${{\bf{O}}}_{{\bf{2}}}^{{\boldsymbol{\cdot }}{\boldsymbol{-}}}$$ O2⋅− ) produced by dysfunctional mitochondria is a key pathogenic event of aging and ischemia-reperfusion diseases. Here, a new $${{\bf{O}}}_{{\bf{2}}}^{{\boldsymbol{\cdot }}{\boldsymbol{-}}}$$ O2⋅− -scavenging MnII complex with a new polyamino-polycarboxylate macrocycle (4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diacetate) containing 2 quinoline units (MnQ2), designed to improve complex stability and cell permeability, was compared to parental MnII complex with methyls replacing quinolines (MnM2). MnQ2 was more stable than MnM2 (log K = 19.56(8) vs. 14.73(2) for the equilibrium Mn2+ + L2−, where L = Q2 and M2) due to the involvement of quinoline in metal binding and to the hydrophobic features of the ligand which improve metal desolvation upon complexation. As oxidative stress model, H9c2 rat cardiomyoblasts were subjected to hypoxia-reoxygenation. MnQ2 and MnM2 (10 μmol L−1) were added at reoxygenation for 1 or 2 h. The more lipophilic MnQ2 showed more rapid cell and mitochondrial penetration than MnM2. Both MnQ2 and MnM2 abated endogenous ROS and mitochondrial $${{\bf{O}}}_{{\bf{2}}}^{{\boldsymbol{\cdot }}{\boldsymbol{-}}}$$ O2⋅− , decreased cell lipid peroxidation, reduced mitochondrial dysfunction, in terms of efficiency of the respiratory chain and preservation of membrane potential (Δψ) and permeability, decreased the activation of pro-apoptotic caspases 9 and 3, and increased cell viability. Of note, MnQ2 was more effective than MnM2 to exert cytoprotective anti-oxidant effects in the short term. Compounds with redox-inert ZnII replacing the functional MnII were ineffective. This study provides clues which further our understanding of the structure-activity relationships of MnII-chelates and suggests that MnII-polyamino-polycarboxylate macrocycles could be developed as new anti-oxidant drugs.
format	article
author	Matteo Becatti Andrea Bencini Silvia Nistri Luca Conti Maria Giulia Fabbrini Laura Lucarini Veronica Ghini Mirko Severi Claudia Fiorillo Claudia Giorgi Lorenzo Sorace Barbara Valtancoli Daniele Bani
author_facet	Matteo Becatti Andrea Bencini Silvia Nistri Luca Conti Maria Giulia Fabbrini Laura Lucarini Veronica Ghini Mirko Severi Claudia Fiorillo Claudia Giorgi Lorenzo Sorace Barbara Valtancoli Daniele Bani
author_sort	Matteo Becatti
title	Different Antioxidant Efficacy of Two MnII-Containing Superoxide Anion Scavengers on Hypoxia/Reoxygenation-Exposed Cardiac Muscle Cells
title_short	Different Antioxidant Efficacy of Two MnII-Containing Superoxide Anion Scavengers on Hypoxia/Reoxygenation-Exposed Cardiac Muscle Cells
title_full	Different Antioxidant Efficacy of Two MnII-Containing Superoxide Anion Scavengers on Hypoxia/Reoxygenation-Exposed Cardiac Muscle Cells
title_fullStr	Different Antioxidant Efficacy of Two MnII-Containing Superoxide Anion Scavengers on Hypoxia/Reoxygenation-Exposed Cardiac Muscle Cells
title_full_unstemmed	Different Antioxidant Efficacy of Two MnII-Containing Superoxide Anion Scavengers on Hypoxia/Reoxygenation-Exposed Cardiac Muscle Cells
title_sort	different antioxidant efficacy of two mnii-containing superoxide anion scavengers on hypoxia/reoxygenation-exposed cardiac muscle cells
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/04182cdca23f47ec9e1ab153252d5613
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Different Antioxidant Efficacy of Two MnII-Containing Superoxide Anion Scavengers on Hypoxia/Reoxygenation-Exposed Cardiac Muscle Cells

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