| First Author | Li SY | Year | 2006 |
| Journal | Diabetologia | Volume | 49 |
| Issue | 6 | Pages | 1434-46 |
| PubMed ID | 16612592 | Mgi Jnum | J:111488 |
| Mgi Id | MGI:3654215 | Doi | 10.1007/s00125-006-0229-0 |
| Citation | Li SY, et al. (2006) Cardiac contractile dysfunction in Lep/Lep obesity is accompanied by NADPH oxidase activation, oxidative modification of sarco(endo)plasmic reticulum Ca(2+)-ATPase and myosin heavy chain isozyme switch. Diabetologia 49(6):1434-46 |
| abstractText | 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 Ca(2+)-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 (TR(50), TR(90)), maximal velocity of shortening/relengthening (+/-dL/dt), intracellular Ca(2+) and its decay (tau). Oxidative stress, lipid peroxidation, protein damage and SERCA activity were assessed by glutathione/glutathione disulfide, malondialdehyde, protein carbonyl and (45)Ca(2+) uptake, respectively. NADPH oxidase was determined by immunoblotting. RESULTS: Myocytes from Lep/Lep mice displayed depressed PS and +/- dL/dt, prolonged TR(50), TR(90), elevated resting [Ca(2+)](i), prolonged tau, reduced contractile capacity at high stimulus frequencies and diminished responsiveness to extracellular Ca(2+) 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 (45)Ca(2+) 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 (45)Ca(2+) 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. |
