Abstract
IntroductionNicotinamide adenine dinucleotide phosphate (NADPH) oxidases are responsible for the generation of reactive oxygen species, producing vascular and myocardial dysfunction in diabetes mellitus. However, the potential benefits of the NADPH oxidase inhibitor, apocynin, on left ventricular (LV) remodeling remain unknown.ResultsIn the diabetic group, interventricular septal thickness and left ventricular posterior wall thickness were markedly increased compared to control. These changes were accompanied by increased LV cardiomyocyte cross-sectional area and greater degree of interstitial fibrosis. NO, myeloperoxidase, and malonaldehyde levels in the serum were significantly increased Moreover, protein expression levels of rac1, nuclear factor-κB, transforming growth factor-β, p38, P-p38, and metalloproteinase-9 were also raised. Apocynin treatment prevented all of these structural, histological and biochemical changes and additionally increased superoxide dismutase levels.MethodsThirty Japanese rabbits were randomized into three groups: control, alloxan-induced diabetes with and without apocynin treatment at 15 mg/kg/day for 8 weeks (n = 10 for each group). Echocardiography was performed and hemodynamics were assessed by carotid and LV catheterization. LV cardiomyocyte cross-sectional area and interstitial fibrosis were evaluated by histology. Serum nitric oxide (NO), malonaldehyde, myeloperoxidase, superoxide dismutase (SOD) levels, and activity of LV tissue NADPH oxidases was assessed. Expression of proteins involved in pro-inflammatory and pro-fibrotic signaling were determined by Western blotting.ConclusionsInhibition of NADPH oxidase using apocynin is an effective upstream therapy for preventing diabetes-induced adverse remodeling of the left ventricular myocardium.
Highlights
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are responsible for the generation of reactive oxygen species, producing vascular and myocardial dysfunction in diabetes mellitus
These changes were accompanied by increased left ventricular (LV) cardiomyocyte cross-sectional area and greater degree of interstitial fibrosis
Our initial experiments confirmed that alloxan successfully induced diabetes in the rabbits after 6 weeks, leading to lower body weight, increased glucose levels and decreased insulin levels compared to control (Table 1) (P < 0.05)
Summary
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are responsible for the generation of reactive oxygen species, producing vascular and myocardial dysfunction in diabetes mellitus. Especially if glycemic control is poor, causes damage to multiple organ systems, leading to significant morbidity and mortality. It can result in cardiac hypertrophy, cardiomyopathy and heart failure [2, 3]. Recent research efforts have focused on elucidating the molecular mechanisms by which increased oxidative stress is generated in diabetes, and how this leads to vascular and cardiac dysfunction [7,8,9]. Reactive oxidant species (ROS) can promote cardiac hypertrophy, fibrosis, contractile dysfunction and eventually pump failure [14]. The primary sources of ROS include the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, mitochondria, xanthine oxidases, and uncoupled NO synthases (NOS) [14], while NADPH oxidase (NOX) activates redox signaling, in turn causing tissue injury [15, 16]
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