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Antioxidant N‐acetylcysteine restores myocardial Mn‐SOD activity and attenuates left ventricular diastolic dysfunction in diabetic rats
Author(s) -
Xia Zhengyuan,
Guo Zhixin,
Yuen Violet G.,
Jiang Jihong,
McNeill John H.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a231
Subject(s) - antioxidant , medicine , diastole , cardiology , acetylcysteine , chemistry , blood pressure , biochemistry
Manganese‐containing superoxide dismutase (Mn‐SOD) plays a critical role in guarding against mitochondrial oxidative stress (OS). Abnormal myocardial mitochondrial metabolism of reactive oxygen species plays an important role in the pathogenesis of diabetic cardiac dysfunction. We hypothesized that chronic treatment with N‐acetylcysteine (NAC), an antioxidant, would normalize hyperglycemia induced inactivation of Mn‐SOD and attenuate myocardial dysfunction. Control and streptozotozin‐induced diabetic rats were treated (CT, DT) or untreated (C, D) with NAC in drinking water for 8 weeks. Myocardial Mn‐SOD activity, but not Mn‐SOD protein expression, in D rats was significantly reduced while levels of OS as determined by myocardial free 15‐F2t‐isoprostane was increased as compared to all other groups. This was accompanied by increased membrane translocation of p67phox, a cytosolic subunit of the NAD(P)H oxidase whose activation may contribute to the elevated OS in diabetes. A decrease in left ventricular maximum relaxation (‐dP/dT) and an increase in the t1/2 to maximum relaxation were found in D rats. NAC normalized or attenuated the changes seen in D group. The results suggest that OS‐mediated inactivation of myocardial Mn‐SOD may contribute to the development of myocardial diastolic dysfunction in diabetes. This study was funded by GIA from Canadian Diabetes Association and a Program Grant from the Heart & Stroke Foundation of BC and Yukon, Canada. ZX and JJ are supported by CIHR/Rx &D HRF.