Multiple Antioxidants Improve Cardiac Complications and Inhibit Cardiac Cell Death in Streptozotocin-Induced Diabetic Rats

Santosh Kumar,Sahdeo Prasad,Sandhya L Sitasawad

doi:10.1371/journal.pone.0067009

Abstract

Diabetic cardiomyopathy, a disorder of the heart muscle in diabetic patients, is one of the major causes of heart failure. Since diabetic cardiomyopathy is now known to have a high prevalence in the asymptomatic diabetic patient, prevention at the earliest stage of development by existing molecules would be appropriate in order to prevent the progression of heart failure. In this study, we investigated the protective role of multiple antioxidants (MA), on cardiac dysfunction and cardiac cell apoptosis in streptozotocin (STZ)-induced diabetic rat. Diabetic cardiomyopathy in STZ-treated animals was characterized by declined systolic, diastolic myocardial performance, oxidative stress and apoptosis in cardiac cells. Diabetic rats on supplementation with MA showed decreased oxidative stress evaluated by the content of reduced levels of lipid per-oxidation and decreased activity of catalase with down-regulation of heme-oxygenase-1 mRNA. Supplementation with MA also resulted in a normalized lipid profile and decreased levels of pro-inflammatory transcription factor NF-kappaB as well as cytokines such as TNF-α, IFN-γ, TGF-β, and IL-10. MA was found to decrease the expression of ROS-generating enzymes like xanthine oxidase, monoamine oxidase-A along with 5-Lipoxygenase mRNA and/or protein expression. Further, left ventricular function, measured by a microtip pressure transducer, was re-established as evidenced by increase in ±dp/dtmax, heart rate, decreased blood pressure, systolic and diastolic pressure as well as decrease in the TUNEL positive cardiac cells with increased Bcl-2/Bax ratio. In addition, MA supplementation decreased cell death and activation of NF-kappaB in cardiac H9c2 cells. Based on our results, we conclude that MA supplementation significantly attenuated cardiac dysfunction in diabetic rats; hence MA supplementation may have important clinical implications in terms of prevention and management of diabetic cardiomyopathy.

Highlights

Cardiomyopathy, a severely disabling complication of diabetes mellitus, is the leading cause of mortality among adults throughout the world [1]
We have investigated the fate of diabetes on cardiac cells and assessed the protective role of multiple antioxidants (MA) in diabetic cardiomyopathy of animal model
We found that STZ-induced diabetes resulted in markedly increased cholesterol (99.66762.789 vs. 81.33362.871 mg/dl, n = 6, P,0.05) and triglyceride (138.667612.837 vs. 67.16765.056 mg/dl, n = 6, P,0.05) levels in the serum compared with the controls

Summary

Introduction

Cardiomyopathy, a severely disabling complication of diabetes mellitus, is the leading cause of mortality among adults throughout the world [1]. People with cardiomyopathy are often at a risk of suffering from irregular heart beat and sudden cardiac death. Oxidative and nitrosative stress induced by reactive oxygen species (ROS) and reactive nitrogen species (RNS) derived from hyperglycemia in the diabetic heart is considered to be a contributing factor in the development and the progression of diabetic cardiomyopathy [2,3]. The mechanism by which oxidative stress might impair cardiac function involves oxidative damage to cellular proteins and membranes, thereby, inducing cellular dysfunction or death [4]. It has been reported that increased ROS causes cell death through the activation of maladaptive signaling pathways, which could contribute to the pathogenesis of diabetic cardiomyopathy [5]. Evidence for increased ROS production in diabetes mellitus is reasonably strong [2,3] the patho-physiological relevance of increased myocardial ROS production in diabetes remains to be further characterized

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Conclusion