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Folic acid reduces doxorubicin-induced cardiomyopathy by modulating endothelial nitric oxide synthase.
J Cell Mol Med 2017; 21(12):3277-3287JC

Abstract

The use of doxorubicin (DOXO) as a chemotherapeutic drug has been hampered by cardiotoxicity leading to cardiomyopathy and heart failure. Folic acid (FA) is a modulator of endothelial nitric oxide (NO) synthase (eNOS), which in turn is an important player in diseases associated with NO insufficiency or NOS dysregulation, such as pressure overload and myocardial infarction. However, the role of FA in DOXO-induced cardiomyopathy is poorly understood. The aim of this study was to test the hypothesis that FA prevents DOXO-induced cardiomyopathy by modulating eNOS and mitochondrial structure and function. Male C57BL/6 mice were randomized to a single dose of DOXO (20 mg/kg intraperitoneal) or sham. FA supplementation (10 mg/day per oral) was started 7 days before DOXO injection and continued thereafter. DOXO resulted in 70% mortality after 10 days, with the surviving mice demonstrating a 30% reduction in stroke volume compared with sham groups. Pre-treatment with FA reduced mortality to 45% and improved stroke volume (both P < 0.05 versus DOXO). These effects of FA were underlain by blunting of DOXO-induced cardiomyocyte atrophy, apoptosis, interstitial fibrosis and impairment of mitochondrial function. Mechanistically, pre-treatment with FA prevented DOXO-induced increases in superoxide anion production by reducing the eNOS monomer:dimer ratio and eNOS S-glutathionylation, and attenuated DOXO-induced decreases in superoxide dismutase, eNOS phosphorylation and NO production. Enhancing eNOS function by restoring its coupling and subsequently reducing oxidative stress with FA may be a novel therapeutic approach to attenuate DOXO-induced cardiomyopathy.

Authors+Show Affiliations

Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands.Institute of Gender in Medicine and Center for Cardiovascular Research, Charite University Hospital, Berlin, Germany. DZHK (German Centre for Cardiovascular Research), Berlin, Germany.Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands.Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.Electron Microscopy Unit, CRISP and Department of Molecular Cell Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.Electron Microscopy Unit, CRISP and Department of Molecular Cell Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.Institute of Gender in Medicine and Center for Cardiovascular Research, Charite University Hospital, Berlin, Germany.Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28608983

Citation

Octavia, Yanti, et al. "Folic Acid Reduces Doxorubicin-induced Cardiomyopathy By Modulating Endothelial Nitric Oxide Synthase." Journal of Cellular and Molecular Medicine, vol. 21, no. 12, 2017, pp. 3277-3287.
Octavia Y, Kararigas G, de Boer M, et al. Folic acid reduces doxorubicin-induced cardiomyopathy by modulating endothelial nitric oxide synthase. J Cell Mol Med. 2017;21(12):3277-3287.
Octavia, Y., Kararigas, G., de Boer, M., Chrifi, I., Kietadisorn, R., Swinnen, M., ... Moens, A. L. (2017). Folic acid reduces doxorubicin-induced cardiomyopathy by modulating endothelial nitric oxide synthase. Journal of Cellular and Molecular Medicine, 21(12), pp. 3277-3287. doi:10.1111/jcmm.13231.
Octavia Y, et al. Folic Acid Reduces Doxorubicin-induced Cardiomyopathy By Modulating Endothelial Nitric Oxide Synthase. J Cell Mol Med. 2017;21(12):3277-3287. PubMed PMID: 28608983.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Folic acid reduces doxorubicin-induced cardiomyopathy by modulating endothelial nitric oxide synthase. AU - Octavia,Yanti, AU - Kararigas,Georgios, AU - de Boer,Martine, AU - Chrifi,Ihsan, AU - Kietadisorn,Rinrada, AU - Swinnen,Melissa, AU - Duimel,Hans, AU - Verheyen,Fons K, AU - Brandt,Maarten M, AU - Fliegner,Daniela, AU - Cheng,Caroline, AU - Janssens,Stefan, AU - Duncker,Dirk J, AU - Moens,An L, Y1 - 2017/06/13/ PY - 2017/02/11/received PY - 2017/04/13/accepted PY - 2017/6/14/pubmed PY - 2018/7/11/medline PY - 2017/6/14/entrez KW - anthracycline KW - antioxidant enzyme KW - cardiotoxicity KW - free radical KW - nitric oxide SP - 3277 EP - 3287 JF - Journal of cellular and molecular medicine JO - J. Cell. Mol. Med. VL - 21 IS - 12 N2 - The use of doxorubicin (DOXO) as a chemotherapeutic drug has been hampered by cardiotoxicity leading to cardiomyopathy and heart failure. Folic acid (FA) is a modulator of endothelial nitric oxide (NO) synthase (eNOS), which in turn is an important player in diseases associated with NO insufficiency or NOS dysregulation, such as pressure overload and myocardial infarction. However, the role of FA in DOXO-induced cardiomyopathy is poorly understood. The aim of this study was to test the hypothesis that FA prevents DOXO-induced cardiomyopathy by modulating eNOS and mitochondrial structure and function. Male C57BL/6 mice were randomized to a single dose of DOXO (20 mg/kg intraperitoneal) or sham. FA supplementation (10 mg/day per oral) was started 7 days before DOXO injection and continued thereafter. DOXO resulted in 70% mortality after 10 days, with the surviving mice demonstrating a 30% reduction in stroke volume compared with sham groups. Pre-treatment with FA reduced mortality to 45% and improved stroke volume (both P < 0.05 versus DOXO). These effects of FA were underlain by blunting of DOXO-induced cardiomyocyte atrophy, apoptosis, interstitial fibrosis and impairment of mitochondrial function. Mechanistically, pre-treatment with FA prevented DOXO-induced increases in superoxide anion production by reducing the eNOS monomer:dimer ratio and eNOS S-glutathionylation, and attenuated DOXO-induced decreases in superoxide dismutase, eNOS phosphorylation and NO production. Enhancing eNOS function by restoring its coupling and subsequently reducing oxidative stress with FA may be a novel therapeutic approach to attenuate DOXO-induced cardiomyopathy. SN - 1582-4934 UR - https://www.unboundmedicine.com/medline/citation/28608983/Folic_acid_reduces_doxorubicin_induced_cardiomyopathy_by_modulating_endothelial_nitric_oxide_synthase_ L2 - https://doi.org/10.1111/jcmm.13231 DB - PRIME DP - Unbound Medicine ER -