title: 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.
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
authors.forename: Niraj M
authors.initials: NM
authors.lastname: Bhatt
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Aon
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
authors.forename: Carlo G
authors.initials: CG
authors.lastname: Tocchetti
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Shen
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
authors.forename: Swati
authors.initials: S
authors.lastname: Dey
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
authors.forename: Genaro
authors.initials: G
authors.lastname: Ramirez-Correa
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
authors.forename: Brian
authors.initials: B
authors.lastname: O'Rourke
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Wei Dong
authors.initials: WD
authors.lastname: Gao
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and scortas1@jhmi.edu.
authors.forename: Sonia
authors.initials: S
authors.lastname: Cortassa
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000503:physiopathology; D058065:Diabetic Cardiomyopathies / Q000378:metabolism* / Q000503:physiopathology; D005978:Glutathione / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010101:Oxygen Consumption; D010168:Palmitates / Q000097:blood / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D013879:Thioredoxins / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; D010168:Palmitates; D013879:Thioredoxins; D005978:Glutathione
keywords: Zucker diabetic fatty rat; antioxidant systems; contractile work; mitochondrial ros emission; oxidative phosphorylation; rate of respiration; redox environment