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Restoring redox balance enhances contractility in heart trabeculae from type 2 diabetic rats exposed to high glucose.

Abstract

Hearts from type 2 diabetic (T2DM) subjects are chronically subjected to hyperglycemia and hyperlipidemia, both thought to contribute to oxidizing conditions and contractile dysfunction. How redox alterations and contractility interrelate, ultimately diminishing T2DM heart function, remains poorly understood. Herein we tested whether the fatty acid palmitate (Palm), in addition to its energetic contribution, rescues function by improving redox [glutathione (GSH), NAD(P)H, less oxidative stress] in T2DM rat heart trabeculae subjected to high glucose. Using cardiac trabeculae from Zucker Diabetic Fatty (ZDF) rats, we assessed the impact of low glucose (EG) and high glucose (HG), in absence or presence of Palm or insulin, on force development, energetics, and redox responses. We found that in EG ZDF and lean trabeculae displayed similar contractile work, yield of contractile work (Ycw), representing the ratio of force time integral over rate of O2 consumption. Conversely, HG had a negative impact on Ycw, whereas Palm, but not insulin, completely prevented contractile loss. This effect was associated with higher GSH, less oxidative stress, and augmented matrix GSH/thioredoxin (Trx) in ZDF mitochondria. Restoration of myocardial redox with GSH ethyl ester also rescued ZDF contractile function in HG, independently from Palm. These results support the idea that maintained redox balance, via increased GSH and Trx antioxidant activities to resist oxidative stress, is an essential protective response of the diabetic heart to keep contractile function.

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  • Authors+Show Affiliations

    ,

    Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.

    ,

    Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.

    ,

    Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.

    ,

    Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

    ,

    Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.

    ,

    Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.

    ,

    Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.

    ,

    Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

    Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and scortas1@jhmi.edu.

    Source

    MeSH

    Animals
    Blood Glucose
    Diabetes Mellitus, Type 2
    Diabetic Cardiomyopathies
    Glutathione
    Heart
    Insulin
    Mitochondria, Heart
    Myocardial Contraction
    Myocardium
    Myocytes, Cardiac
    Oxidation-Reduction
    Oxidative Stress
    Oxygen Consumption
    Palmitates
    Rats
    Rats, Zucker
    Thioredoxins

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    25485897

    Citation

    Bhatt, Niraj M., et al. "Restoring Redox Balance Enhances Contractility in Heart Trabeculae From Type 2 Diabetic Rats Exposed to High Glucose." American Journal of Physiology. Heart and Circulatory Physiology, vol. 308, no. 4, 2015, pp. H291-302.
    Bhatt NM, Aon MA, Tocchetti CG, et al. Restoring redox balance enhances contractility in heart trabeculae from type 2 diabetic rats exposed to high glucose. Am J Physiol Heart Circ Physiol. 2015;308(4):H291-302.
    Bhatt, N. M., Aon, M. A., Tocchetti, C. G., Shen, X., Dey, S., Ramirez-Correa, G., ... Cortassa, S. (2015). Restoring redox balance enhances contractility in heart trabeculae from type 2 diabetic rats exposed to high glucose. American Journal of Physiology. Heart and Circulatory Physiology, 308(4), pp. H291-302. doi:10.1152/ajpheart.00378.2014.
    Bhatt NM, et al. Restoring Redox Balance Enhances Contractility in Heart Trabeculae From Type 2 Diabetic Rats Exposed to High Glucose. Am J Physiol Heart Circ Physiol. 2015 Feb 15;308(4):H291-302. PubMed PMID: 25485897.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Restoring redox balance enhances contractility in heart trabeculae from type 2 diabetic rats exposed to high glucose. AU - Bhatt,Niraj M, AU - Aon,Miguel A, AU - Tocchetti,Carlo G, AU - Shen,Xiaoxu, AU - Dey,Swati, AU - Ramirez-Correa,Genaro, AU - O'Rourke,Brian, AU - Gao,Wei Dong, AU - Cortassa,Sonia, Y1 - 2014/12/05/ PY - 2014/12/9/entrez PY - 2014/12/9/pubmed PY - 2015/4/14/medline KW - Zucker diabetic fatty rat KW - antioxidant systems KW - contractile work KW - mitochondrial ros emission KW - oxidative phosphorylation KW - rate of respiration KW - redox environment SP - H291 EP - 302 JF - American journal of physiology. Heart and circulatory physiology JO - Am. J. Physiol. Heart Circ. Physiol. VL - 308 IS - 4 N2 - Hearts from type 2 diabetic (T2DM) subjects are chronically subjected to hyperglycemia and hyperlipidemia, both thought to contribute to oxidizing conditions and contractile dysfunction. How redox alterations and contractility interrelate, ultimately diminishing T2DM heart function, remains poorly understood. Herein we tested whether the fatty acid palmitate (Palm), in addition to its energetic contribution, rescues function by improving redox [glutathione (GSH), NAD(P)H, less oxidative stress] in T2DM rat heart trabeculae subjected to high glucose. Using cardiac trabeculae from Zucker Diabetic Fatty (ZDF) rats, we assessed the impact of low glucose (EG) and high glucose (HG), in absence or presence of Palm or insulin, on force development, energetics, and redox responses. We found that in EG ZDF and lean trabeculae displayed similar contractile work, yield of contractile work (Ycw), representing the ratio of force time integral over rate of O2 consumption. Conversely, HG had a negative impact on Ycw, whereas Palm, but not insulin, completely prevented contractile loss. This effect was associated with higher GSH, less oxidative stress, and augmented matrix GSH/thioredoxin (Trx) in ZDF mitochondria. Restoration of myocardial redox with GSH ethyl ester also rescued ZDF contractile function in HG, independently from Palm. These results support the idea that maintained redox balance, via increased GSH and Trx antioxidant activities to resist oxidative stress, is an essential protective response of the diabetic heart to keep contractile function. SN - 1522-1539 UR - https://www.unboundmedicine.com/medline/citation/25485897/Restoring_redox_balance_enhances_contractility_in_heart_trabeculae_from_type_2_diabetic_rats_exposed_to_high_glucose_ L2 - http://www.physiology.org/doi/full/10.1152/ajpheart.00378.2014?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -