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.
Highlights
Cardiomyopathy and other cardiovascular complications associated with increased inflammatory and oxidative stress responses are the major causes of accelerated atherosclerosis, obesity and diabetes [1,2,3]
Catalase activity was found to be significantly activated (Figure 1D). These results suggest that catalase appears to be the main enzyme involved in H2O2 clearance as we observed no marked alteration in GSH-Px activity in Zucker diabetic fatty (ZDF) rats
A significant decrease in activity of the terminal respiratory enzyme, cytochrome c oxidase (Complex IV), was observed in ZDF rat hearts (Figure 4B). These results have clearly suggested that mitochondrial bioenergetics (ATP production) is affected in the cardiac myocytes of ZDF rats
Summary
Cardiomyopathy and other cardiovascular complications associated with increased inflammatory and oxidative stress responses are the major causes of accelerated atherosclerosis, obesity and diabetes [1,2,3]. Our previous studies, using both type 1 and type 2 diabetic models, have suggested that myocardial Ca2+ signaling genes and proteins have been drastically affected in diabetes and obesity related complications [11,12,13,14] In these studies, it is not clear if these changes are in response to increased oxidative stress due to increased reactive oxygen species (ROS). Our previous studies, using in vivo type 1 diabetes models have strongly suggested increased oxidative stress, mitochondrial dysfunction and compromised energy and GSH metabolism in chronic diabetic complications [15,16,17,18]. Our results have provided a better insight of the etiology and pathology of diabetes and obesity associated complications and have implications in designing therapeutic approaches
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