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  • Title: Cardiac contractile dysfunction in Lep/Lep obesity is accompanied by NADPH oxidase activation, oxidative modification of sarco(endo)plasmic reticulum Ca2+-ATPase and myosin heavy chain isozyme switch.
    Author: Li SY, Yang X, Ceylan-Isik AF, Du M, Sreejayan N, Ren J.
    Journal: Diabetologia; 2006 Jun; 49(6):1434-46. PubMed ID: 16612592.
    Abstract:
    AIMS/HYPOTHESIS: Obesity is an independent risk factor for heart diseases but the underlying mechanism is not clear. This study examined cardiac contraction, oxidative stress, oxidative modification of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) and the myosin heavy chain (MHC) isoform switch in obese mice. METHODS: Mechanical properties were evaluated in ventricular myocytes from C57BL/6J lean and Lep/Lep obese mice (formerly known as ob/ob mice), including peak shortening (PS), time to 50 or 90% PS, time to 50 or 90% relengthening (TR50, TR90), maximal velocity of shortening/relengthening (+/-dL/dt), intracellular Ca2+ and its decay (tau). Oxidative stress, lipid peroxidation, protein damage and SERCA activity were assessed by glutathione/glutathione disulfide, malondialdehyde, protein carbonyl and 45Ca2+ uptake, respectively. NADPH oxidase was determined by immunoblotting. RESULTS: Myocytes from Lep/Lep mice displayed depressed PS and +/- dL/dt, prolonged TR50, TR90, elevated resting [Ca2+]i, prolonged tau, reduced contractile capacity at high stimulus frequencies and diminished responsiveness to extracellular Ca2+ compared with lean controls. Cardiac glutathione/glutathione disulfide was decreased whereas malondialdehyde, protein carbonyl, membrane p47(phox) and membrane gp91(phox) were increased in the Lep/Lep group. SERCA isoenzyme 2a was markedly modified by oxidation in Lep/Lep hearts and associated with decreased 45Ca2+ uptake. The MHC isozyme displayed a shift from the alpha to the beta isoform in Lep/Lep hearts. Short-term incubation of angiotensin II with myocytes mimicked the mechanical defects, SERCA oxidation and 45Ca2+ uptake seen in Lep/Lep myocytes. Incubation of the NADPH oxidase inhibitor apocynin with Lep/Lep myocytes alleviated contractile defects without reversing SERCA oxidation or activity. CONCLUSIONS/INTERPRETATION: These data indicate that obesity-related cardiac defects may be related to NADPH oxidase activation, oxidative damage to SERCA and the MHC isozyme switch.
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