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Impaired mitochondrial energy supply coupled to increased H2O2 emission under energy/redox stress leads to myocardial dysfunction during Type I diabetes.
Clin Sci (Lond) 2015; 129(7):561-74CS

Abstract

In Type I diabetic (T1DM) patients, both peaks of hyperglycaemia and increased sympathetic tone probably contribute to impair systolic and diastolic function. However, how these stressors eventually alter cardiac function during T1DM is not fully understood. In the present study, we hypothesized that impaired mitochondrial energy supply and excess reactive oxygen species (ROS) emission is centrally involved in T1DM cardiac dysfunction due to metabolic/redox stress and aimed to determine the mitochondrial sites implicated in these alterations. To this end, we used isolated myocytes and mitochondria from Sham and streptozotocin (STZ)-induced T1DM guinea pigs (GPs), untreated or treated with insulin. Relative to controls, T1DM myocytes exhibited higher oxidative stress when challenged with high glucose (HG) combined with β-adrenergic stimulation [via isoprenaline (isoproterenol) (ISO)], leading to contraction/relaxation deficits. T1DM mitochondria had decreased respiration with complex II and IV substrates and markedly lower ADP phosphorylation rates and higher H2O2 emission when challenged with oxidants to mimic the more oxidized redox milieu present in HG + ISO-treated cardiomyocytes. Since in T1DM hearts insulin-sensitivity is preserved and a glucose-to-fatty acid (FA) shift occurs, we next tested whether insulin therapy or acute palmitate (Palm) infusion prevents HG + ISO-induced cardiac dysfunction. We found that insulin rescued proper cardiac redox balance, but not mitochondrial respiration or contractile performance. Conversely, Palm restored redox balance and preserved myocyte function. Thus, stressors such as peaks of HG and adrenergic hyperactivity impair mitochondrial respiration, hampering energy supply while exacerbating ROS emission. Our study suggests that an ideal therapeutic measure to treat metabolically/redox-challenged T1DM hearts should concomitantly correct energetic and redox abnormalities to fully maintain cardiac function.

Authors+Show Affiliations

Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, U.S.A. Department of Translational Medical Sciences, Division of Internal Medicine, Federico II University, Naples, NA 80131, Italy.Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, U.S.A.Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, U.S.A.Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, U.S.A. Australian School of Advanced Medicine, Macquarie University, Sydney, NSW 2109, Australia.Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, U.S.A.Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, U.S.A.Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, U.S.A.Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, U.S.A. maon1@jhmi.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26186741

Citation

Tocchetti, Carlo G., et al. "Impaired Mitochondrial Energy Supply Coupled to Increased H2O2 Emission Under Energy/redox Stress Leads to Myocardial Dysfunction During Type I Diabetes." Clinical Science (London, England : 1979), vol. 129, no. 7, 2015, pp. 561-74.
Tocchetti CG, Stanley BA, Sivakumaran V, et al. Impaired mitochondrial energy supply coupled to increased H2O2 emission under energy/redox stress leads to myocardial dysfunction during Type I diabetes. Clin Sci. 2015;129(7):561-74.
Tocchetti, C. G., Stanley, B. A., Sivakumaran, V., Bedja, D., O'Rourke, B., Paolocci, N., ... Aon, M. A. (2015). Impaired mitochondrial energy supply coupled to increased H2O2 emission under energy/redox stress leads to myocardial dysfunction during Type I diabetes. Clinical Science (London, England : 1979), 129(7), pp. 561-74. doi:10.1042/CS20150204.
Tocchetti CG, et al. Impaired Mitochondrial Energy Supply Coupled to Increased H2O2 Emission Under Energy/redox Stress Leads to Myocardial Dysfunction During Type I Diabetes. Clin Sci. 2015;129(7):561-74. PubMed PMID: 26186741.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Impaired mitochondrial energy supply coupled to increased H2O2 emission under energy/redox stress leads to myocardial dysfunction during Type I diabetes. AU - Tocchetti,Carlo G, AU - Stanley,Brian A, AU - Sivakumaran,Vidhya, AU - Bedja,Djahida, AU - O'Rourke,Brian, AU - Paolocci,Nazareno, AU - Cortassa,Sonia, AU - Aon,Miguel A, Y1 - 2015/06/11/ PY - 2015/03/18/received PY - 2015/05/29/accepted PY - 2015/7/18/entrez PY - 2015/7/18/pubmed PY - 2015/10/6/medline KW - adrenergic stimulation KW - calcium transient KW - contractility KW - diabetes KW - energetic transitions KW - glutathione KW - hyperglycaemia KW - redox balance SP - 561 EP - 74 JF - Clinical science (London, England : 1979) JO - Clin. Sci. VL - 129 IS - 7 N2 - In Type I diabetic (T1DM) patients, both peaks of hyperglycaemia and increased sympathetic tone probably contribute to impair systolic and diastolic function. However, how these stressors eventually alter cardiac function during T1DM is not fully understood. In the present study, we hypothesized that impaired mitochondrial energy supply and excess reactive oxygen species (ROS) emission is centrally involved in T1DM cardiac dysfunction due to metabolic/redox stress and aimed to determine the mitochondrial sites implicated in these alterations. To this end, we used isolated myocytes and mitochondria from Sham and streptozotocin (STZ)-induced T1DM guinea pigs (GPs), untreated or treated with insulin. Relative to controls, T1DM myocytes exhibited higher oxidative stress when challenged with high glucose (HG) combined with β-adrenergic stimulation [via isoprenaline (isoproterenol) (ISO)], leading to contraction/relaxation deficits. T1DM mitochondria had decreased respiration with complex II and IV substrates and markedly lower ADP phosphorylation rates and higher H2O2 emission when challenged with oxidants to mimic the more oxidized redox milieu present in HG + ISO-treated cardiomyocytes. Since in T1DM hearts insulin-sensitivity is preserved and a glucose-to-fatty acid (FA) shift occurs, we next tested whether insulin therapy or acute palmitate (Palm) infusion prevents HG + ISO-induced cardiac dysfunction. We found that insulin rescued proper cardiac redox balance, but not mitochondrial respiration or contractile performance. Conversely, Palm restored redox balance and preserved myocyte function. Thus, stressors such as peaks of HG and adrenergic hyperactivity impair mitochondrial respiration, hampering energy supply while exacerbating ROS emission. Our study suggests that an ideal therapeutic measure to treat metabolically/redox-challenged T1DM hearts should concomitantly correct energetic and redox abnormalities to fully maintain cardiac function. SN - 1470-8736 UR - https://www.unboundmedicine.com/medline/citation/26186741/Impaired_mitochondrial_energy_supply_coupled_to_increased_H2O2_emission_under_energy/redox_stress_leads_to_myocardial_dysfunction_during_Type_I_diabetes_ L2 - http://clinsci.org/cgi/pmidlookup?view=long&pmid=26186741 DB - PRIME DP - Unbound Medicine ER -