title: Alterations in glutathione redox metabolism, oxidative stress, and mitochondrial function in the left ventricle of elderly Zucker diabetic fatty rat heart.
abstract: The Zucker diabetic fatty (ZDF) rat is a genetic model in which the homozygous (FA/FA) male animals develop obesity and type 2 diabetes. Morbidity and mortality from cardiovascular complications, due to increased oxidative stress and inflammatory signals, are the hallmarks of type 2 diabetes. The precise molecular mechanism of contractile dysfunction and disease progression remains to be clarified. Therefore, we have investigated molecular and metabolic targets in male ZDF (30--34 weeks old) rat heart compared to age matched Zucker lean (ZL) controls. Hyperglycemia was confirmed by a 4-fold elevation in non-fasting blood glucose (478.43 ± 29.22 mg/dL in ZDF vs. 108.22 ± 2.52 mg/dL in ZL rats). An increase in reactive oxygen species production, lipid peroxidation and oxidative protein carbonylation was observed in ZDF rats. A significant increase in CYP4502E1 activity accompanied by increased protein expression was also observed in diabetic rat heart. Increased expression of other oxidative stress marker proteins, HO-1 and iNOS was also observed. GSH concentration and activities of GSH-dependent enzymes, glutathione S-transferase and GSH reductase, were, however, significantly increased in ZDF heart tissue suggesting a compensatory defense mechanism. The activities of mitochondrial respiratory enzymes, Complex I and Complex IV were significantly reduced in the heart ventricle of ZDF rats in comparison to ZL rats. Western blot analysis has also suggested a decreased expression of IκB-α and phosphorylated-JNK in diabetic heart tissue. Our results have suggested that mitochondrial dysfunction and increased oxidative stress in ZDF rats might be associated, at least in part, with altered NF-κB/JNK dependent redox cell signaling. These results might have implications in the elucidation of the mechanism of disease progression and designing strategies for diabetes prevention.
authors.affiliation: Department of Biochemistry, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, P.O. Box 17666, UAE. h.raza@uaeu.ac.ae.
authors.forename: Haider
authors.initials: H
authors.lastname: Raza
authors.forename: Annie
authors.initials: A
authors.lastname: John
authors.forename: Frank C
authors.initials: FC
authors.lastname: Howarth
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D058065:Diabetic Cardiomyopathies / Q000473:pathology / Q000503:physiopathology; D018450:Disease Progression; D005978:Glutathione / Q000378:metabolism*; D006352:Heart Ventricles / Q000503:physiopathology / Q000648:ultrastructure; D008297:Male; D008929:Mitochondria, Heart / Q000473:pathology / Q000502:physiology*; D009765:Obesity / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D011924:Rats, Zucker
chemical_list: D005978:Glutathione