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Vitamin C mitigates oxidative/nitrosative stress and inflammation in doxorubicin-induced cardiomyopathy.

Abstract

Increase in oxidative/nitrosative stress is one of the mechanisms associated with the development of cardiotoxicity due to doxorubicin (Dox), a potent chemotherapy drug. Previously, we reported mitigation of Dox-induced oxidative/nitrosative stress and apoptosis by vitamin C (Vit C) in isolated cardiomyocytes. In the present in vivo study in rats, we investigated the effect of prophylactic treatment with Vit C on Dox-induced apoptosis, inflammation, oxidative/nitrosative stress, cardiac dysfunction, and Vit C transporter proteins. Dox (cumulative dose: 15 mg/kg) in rats reduced systolic and diastolic cardiac function and caused structural damage. These changes were associated with a myocardial increase in reactive oxygen species, reduction in antioxidant enzyme activities, increased expression of apoptotic proteins, and inflammation. Dox also caused an increase in the expression of proapoptotic proteins Bax, Bnip-3, Bak, and caspase-3. An increase in oxidative/nitrosative stress attributable to Dox was indicated by an increase in superoxide, protein carbonyl formation, lipid peroxidation, nitric oxide (NO), NO synthase (NOS) activity, protein nitrosylation, and inducible NOS protein expression. Dox increased the levels of cardiac proinflammatory cytokines TNF-α, IL-1β, and IL-6, whereas the expression of Vit C transporter proteins (sodium-ascorbate cotransporter 2 and glucose transporter 4) was reduced. Prophylactic and concurrent treatment with Vit C prevented all these changes and improved survival in the Vit C + Dox group. Vit C also improved Dox-mediated systolic and diastolic dysfunctions and structural damage. These results suggest a cardioprotective role of Vit C in Dox-induced cardiomyopathy by reducing oxidative/nitrosative stress, inflammation, and apoptosis, as well as improving Vit C transporter proteins.NEW & NOTEWORTHY This in vivo study provides novel data that vitamin C improves cardiac structure and function in doxorubicin-induced cardiomyopathy by reducing oxidative/nitrosative stress, apoptosis, and inflammation along with upregulation of cardiac vitamin C transporter proteins. The latter may have a crucial role in improving antioxidant status in this cardiomyopathy.

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  • Authors+Show Affiliations

    ,

    Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.

    ,

    Laboratory of Translational Physiology, Universidade Nove de Julho, São Paulo, Brazil; and.

    ,

    Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.

    ,

    Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.

    ,

    Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.

    ,

    Heart Institute, University of São Paulo Medical School, São Paulo, Brazil.

    ,

    Heart Institute, University of São Paulo Medical School, São Paulo, Brazil.

    ,

    Laboratory of Translational Physiology, Universidade Nove de Julho, São Paulo, Brazil; and.

    Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada; psingal@sbrc.ca.

    Source

    MeSH

    Animals
    Anti-Inflammatory Agents, Non-Steroidal
    Antibiotics, Antineoplastic
    Antioxidants
    Ascorbic Acid
    Cardiomyopathies
    Cardiotonic Agents
    Cytokines
    Doxorubicin
    Electrocardiography
    Male
    Nitric Oxide Synthase
    Oxidative Stress
    Oxygen Consumption
    Rats
    Rats, Wistar
    Reactive Nitrogen Species
    Stress, Physiological
    Survival Analysis

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    28710069

    Citation

    Akolkar, Gauri, et al. "Vitamin C Mitigates Oxidative/nitrosative Stress and Inflammation in Doxorubicin-induced Cardiomyopathy." American Journal of Physiology. Heart and Circulatory Physiology, vol. 313, no. 4, 2017, pp. H795-H809.
    Akolkar G, da Silva Dias D, Ayyappan P, et al. Vitamin C mitigates oxidative/nitrosative stress and inflammation in doxorubicin-induced cardiomyopathy. Am J Physiol Heart Circ Physiol. 2017;313(4):H795-H809.
    Akolkar, G., da Silva Dias, D., Ayyappan, P., Bagchi, A. K., Jassal, D. S., Salemi, V. M. C., ... Singal, P. K. (2017). Vitamin C mitigates oxidative/nitrosative stress and inflammation in doxorubicin-induced cardiomyopathy. American Journal of Physiology. Heart and Circulatory Physiology, 313(4), pp. H795-H809. doi:10.1152/ajpheart.00253.2017.
    Akolkar G, et al. Vitamin C Mitigates Oxidative/nitrosative Stress and Inflammation in Doxorubicin-induced Cardiomyopathy. Am J Physiol Heart Circ Physiol. 2017 Oct 1;313(4):H795-H809. PubMed PMID: 28710069.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Vitamin C mitigates oxidative/nitrosative stress and inflammation in doxorubicin-induced cardiomyopathy. AU - Akolkar,Gauri, AU - da Silva Dias,Danielle, AU - Ayyappan,Prathapan, AU - Bagchi,Ashim K, AU - Jassal,Davinder S, AU - Salemi,Vera Maria Cury, AU - Irigoyen,Maria Claudia, AU - De Angelis,Katia, AU - Singal,Pawan K, Y1 - 2017/07/14/ PY - 2017/05/10/received PY - 2017/06/22/revised PY - 2017/07/06/accepted PY - 2017/7/16/pubmed PY - 2017/10/20/medline PY - 2017/7/16/entrez KW - antioxidant KW - doxorubicin KW - nitrosative stress KW - oxidative stress KW - vitamin C transporter proteins SP - H795 EP - H809 JF - American journal of physiology. Heart and circulatory physiology JO - Am. J. Physiol. Heart Circ. Physiol. VL - 313 IS - 4 N2 - Increase in oxidative/nitrosative stress is one of the mechanisms associated with the development of cardiotoxicity due to doxorubicin (Dox), a potent chemotherapy drug. Previously, we reported mitigation of Dox-induced oxidative/nitrosative stress and apoptosis by vitamin C (Vit C) in isolated cardiomyocytes. In the present in vivo study in rats, we investigated the effect of prophylactic treatment with Vit C on Dox-induced apoptosis, inflammation, oxidative/nitrosative stress, cardiac dysfunction, and Vit C transporter proteins. Dox (cumulative dose: 15 mg/kg) in rats reduced systolic and diastolic cardiac function and caused structural damage. These changes were associated with a myocardial increase in reactive oxygen species, reduction in antioxidant enzyme activities, increased expression of apoptotic proteins, and inflammation. Dox also caused an increase in the expression of proapoptotic proteins Bax, Bnip-3, Bak, and caspase-3. An increase in oxidative/nitrosative stress attributable to Dox was indicated by an increase in superoxide, protein carbonyl formation, lipid peroxidation, nitric oxide (NO), NO synthase (NOS) activity, protein nitrosylation, and inducible NOS protein expression. Dox increased the levels of cardiac proinflammatory cytokines TNF-α, IL-1β, and IL-6, whereas the expression of Vit C transporter proteins (sodium-ascorbate cotransporter 2 and glucose transporter 4) was reduced. Prophylactic and concurrent treatment with Vit C prevented all these changes and improved survival in the Vit C + Dox group. Vit C also improved Dox-mediated systolic and diastolic dysfunctions and structural damage. These results suggest a cardioprotective role of Vit C in Dox-induced cardiomyopathy by reducing oxidative/nitrosative stress, inflammation, and apoptosis, as well as improving Vit C transporter proteins.NEW & NOTEWORTHY This in vivo study provides novel data that vitamin C improves cardiac structure and function in doxorubicin-induced cardiomyopathy by reducing oxidative/nitrosative stress, apoptosis, and inflammation along with upregulation of cardiac vitamin C transporter proteins. The latter may have a crucial role in improving antioxidant status in this cardiomyopathy. SN - 1522-1539 UR - https://www.unboundmedicine.com/medline/citation/28710069/Vitamin_C_mitigates_oxidative/nitrosative_stress_and_inflammation_in_doxorubicin_induced_cardiomyopathy_ L2 - http://www.physiology.org/doi/full/10.1152/ajpheart.00253.2017?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -