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Alterations in glutathione redox metabolism, oxidative stress, and mitochondrial function in the left ventricle of elderly Zucker diabetic fatty rat heart.
Int J Mol Sci 2012; 13(12):16241-54IJ

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+Show Affiliations

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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23203193

Citation

Raza, Haider, et al. "Alterations in Glutathione Redox Metabolism, Oxidative Stress, and Mitochondrial Function in the Left Ventricle of Elderly Zucker Diabetic Fatty Rat Heart." International Journal of Molecular Sciences, vol. 13, no. 12, 2012, pp. 16241-54.
Raza H, John A, Howarth FC. Alterations in glutathione redox metabolism, oxidative stress, and mitochondrial function in the left ventricle of elderly Zucker diabetic fatty rat heart. Int J Mol Sci. 2012;13(12):16241-54.
Raza, H., John, A., & Howarth, F. C. (2012). Alterations in glutathione redox metabolism, oxidative stress, and mitochondrial function in the left ventricle of elderly Zucker diabetic fatty rat heart. International Journal of Molecular Sciences, 13(12), pp. 16241-54. doi:10.3390/ijms131216241.
Raza H, John A, Howarth FC. Alterations in Glutathione Redox Metabolism, Oxidative Stress, and Mitochondrial Function in the Left Ventricle of Elderly Zucker Diabetic Fatty Rat Heart. Int J Mol Sci. 2012 Nov 30;13(12):16241-54. PubMed PMID: 23203193.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Alterations in glutathione redox metabolism, oxidative stress, and mitochondrial function in the left ventricle of elderly Zucker diabetic fatty rat heart. AU - Raza,Haider, AU - John,Annie, AU - Howarth,Frank C, Y1 - 2012/11/30/ PY - 2012/09/20/received PY - 2012/10/31/revised PY - 2012/11/19/accepted PY - 2012/12/4/entrez PY - 2012/12/4/pubmed PY - 2012/12/4/medline SP - 16241 EP - 54 JF - International journal of molecular sciences JO - Int J Mol Sci VL - 13 IS - 12 N2 - 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. SN - 1422-0067 UR - https://www.unboundmedicine.com/medline/citation/23203193/Alterations_in_glutathione_redox_metabolism_oxidative_stress_and_mitochondrial_function_in_the_left_ventricle_of_elderly_Zucker_diabetic_fatty_rat_heart_ L2 - http://www.mdpi.com/resolver?pii=ijms131216241 DB - PRIME DP - Unbound Medicine ER -