Abstract
Brahma-related gene 1 (Brg1) is a key gene in inducing the expression of important endogenous antioxidant enzymes, including heme oxygenase-1 (HO-1) which is central to cardioprotection, while cardiac HO-1 expression is reduced in diabetes. It is unknown whether or not cardiac Brg1 expression is reduced in diabetes. We hypothesize that cardiac Brg1 expression is reduced in diabetes which can be restored by antioxidant treatment with N-acetylcysteine (NAC). Control (C) and streptozotocin-induced diabetic (D) rats were treated with NAC in drinking water or placebo for 4 weeks. Plasma and cardiac free15-F2t-isoprostane in diabetic rats were increased, accompanied with increased plasma levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6), while cardiac Brg1, p-STAT3 and HO-1 protein expression levels were significantly decreased. Left ventricle weight/body weight ratio was higher, while the peak velocities of early (E) and late (A) flow ratio was lower in diabetic than in C rats. NAC normalized tissue and plasma levels of 15-F2t-isoprostane, significantly increased cardiac Brg1, HO-1 and p-STAT3 protein expression levels and reduced TNF-alpha and IL-6, resulting in improved cardiac function. In conclusion, myocardial Brg1 is reduced in diabetes and enhancement of cardiac Brg1 expression may represent a novel mechanism whereby NAC confers cardioprotection.
Highlights
Diabetes mellitus-induced cardiovascular complication is a growing life-threatening disease worldwide
To investigate whether the cardiac protein expression of Brahma-related gene 1 (Brg1) is altered in diabetic rats at an early stage of the disease and whether or not it can be affected by antioxidants, we explored the effects of NAC on cardiac levels of Brg1 in STZ-induced diabetic rats 4 weeks after the establishment of diabetes
Consistent with our previous studies, we have shown in the current study that oxidative stress increased in the early stage rats with STZ-induced type 1 diabetes
Summary
Diabetes mellitus-induced cardiovascular complication is a growing life-threatening disease worldwide. Our previous study found that the major endogenous antioxidant enzyme superoxide dismutase (SOD), which plays an important role in balancing ROS generation and the overall tissue antioxidant capacity, was increased in both the plasma and heart tissue of rats at a relatively early stage (4 weeks) of diabetes, but tissue and plasma levels of free 15-F2tisoprostane, a specific marker of lipid peroxidation, were increased [6]. This indicates that the upregulation of SOD is not sufficient to resist hyperglycemia-induced oxidative stress. The current study was designed to test the hypothesis that myocardial Brg is reduced in diabetes and antioxidant NAC may enhance cardiac Brg expression and concomitantly increase cardiac STAT3 activation and confer cardioprotection in diabetes
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