Different Antioxidant Efficacy of Two MnII-Containing Superoxide Anion Scavengers on Hypoxia/Reoxygenation-Exposed Cardiac Muscle Cells
Autor: | Mirko Severi, Claudia Fiorillo, Daniele Bani, Laura Lucarini, Matteo Becatti, Maria Giulia Fabbrini, Barbara Valtancoli, Luca Conti, Silvia Nistri, Lorenzo Sorace, Claudia Giorgi, Veronica Ghini, Andrea Bencini |
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Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Antioxidant medicine.medical_treatment Science Respiratory chain Ion Metal 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Molecule Multidisciplinary Superoxide Quinoline Cardiac muscle Manganese synthetic enzymes superoxide macrocycle manganese complexes SOD mimetics hypoxia-reoxygenation ischemia-reperfusion injury ROS scavengers Crystallography 030104 developmental biology medicine.anatomical_structure chemistry visual_art visual_art.visual_art_medium Medicine 030217 neurology & neurosurgery |
Zdroj: | Scientific Reports, Vol 9, Iss 1, Pp 1-20 (2019) |
ISSN: | 2045-2322 |
Popis: | Oxidative stress due to excess superoxide anion ($${{\bf{O}}}_{{\bf{2}}}^{{\boldsymbol{\cdot }}{\boldsymbol{-}}}$$ O 2 ⋅ − ) produced by dysfunctional mitochondria is a key pathogenic event of aging and ischemia-reperfusion diseases. Here, a new $${{\bf{O}}}_{{\bf{2}}}^{{\boldsymbol{\cdot }}{\boldsymbol{-}}}$$ O 2 ⋅ − -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 $${{\bf{O}}}_{{\bf{2}}}^{{\boldsymbol{\cdot }}{\boldsymbol{-}}}$$ O 2 ⋅ − , 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. |
Databáze: | OpenAIRE |
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