Downregulation of NADPH oxidase, antioxidant enzymes, and inflammatory markers in the heart of streptozotocin-induced diabetic rats by N-acetyl-l-cysteine

Abstract

We investigated the effect of N-acetyl-l-cysteine (NAC) on the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, antioxidant enzymes, and inflammatory markers in diabetic rat hearts. Metabolic parameters, free 15-F(2t)-isoprostane level, protein expression of NADPH oxidase, superoxide dismutase (SOD), heme oxygenase (HO-1), interleukin-6 (IL-6), and cyclooxygenase-2 (COX-2) were analyzed in control and streptozotocin-induced diabetic rats treated with or without NAC in drinking water for 8 wk. The cardiac protein expression of p67(phox) and p22(phox) was increased in diabetic rats, accompanied by increased NADPH-dependent superoxide production. As a compensatory response to the increased NADPH oxidase, the protein expression of Cu-Zn-SOD and HO-1 and the total SOD activity were also increased in diabetic rat hearts. Consequently, cardiac free 15-F(2t)-isoprostane, an index of oxidative stress, was increased in diabetic rats, indicating that the production of reactive oxygen species becomes excessive in diabetic rat hearts. Cardiac inflammatory markers IL-6 and COX-2 were also increased in diabetic rats. NAC treatment prevented the increased expression of p22(phox) and translocation of p67(phox) to the membrane in diabetic rat hearts. Subsequently, the levels of cardiac free 15-F(2t)-isoprostane, HO-1, Cu-Zn-SOD, total SOD, IL-6, and COX-2 in diabetic rats were decreased by NAC. Consequently, cardiac hypertrophy was attenuated in diabetic rats treated with NAC. The protective effects of NAC on diabetic rat hearts may be attributable to its protection of hearts against oxidative damage induced by the increased NADPH oxidase and to its reduction in cardiac inflammatory mediators IL-6 and COX-2.

Effects of Angiotensin Receptor Blocker on Oxidative Stress and Cardio-Renal Function in Streptozotocin-Induced Diabetic Rats

“…Biomarkers for oxidative damage to DNA, lipids, and proteins also supported the concept of increased oxidative stress in diabetes. 21,22) In the present study, there were a significant increase in MDA level and decrease in SOD activity both in heart and kidney tissue, which were consistent with other reports. 23) These results showed that hyperglycemia caused an imbalance between the production of free radicals and the antioxidant defense system in diabetic conditions.…”

Oxidative stress is not associated with vascular dysfunction in a model of alloxan-induced diabetic rats

“…Taking this into consideration, NAC treatment aiming at reduced MDA levels represents a promising therapeutic opportunity. But, in spite of many reports reassuring its beneficial effect on oxidative stress (22,(32)(33)(34), our study has failed to reduce MDA concentrations. We do not have a clear understanding about the reason why NAC treatment did not restore normal MDA levels, but we hypothesize that this failure could be related to NAC dose or late onset of NAC treatment.…”

NADPH oxidase signaling and cardiac myocyte function

“…Li et al [86] demonstrated that the contractile defect in cardiomyocytes incubated with angiotensin II was abolished by apocynin in association with evidence of reduced activation of Nox2 oxidase. A similar involvement of NADPH-oxidase-derived ROS in cardiomyocyte dysfunction has been suggested in obesity [86], streptozotocin-induced diabetes [87] and [88], aging [89] and gram-negative sepsis [90]. Nox2 is also involved in post-MI contractile dysfunction as discussed in a subsequent section, although this may be secondary to improved remodeling.…”