Alpha-lipoic acid attenuates cardiac fibrosis in Otsuka Long-Evans Tokushima Fatty rats

Jung Eun Lee,Jun Young Choi,Gu Seob Roh,Soo Kyoung Kim,Hyun Joo Shin,Chin-Ok Yi,Tae Sik Jung,Byeong Tak Jeon

doi:10.1186/1475-2840-11-111

Abstract

BackgroundHyperglycemia leads to cardiac oxidative stress and an imbalance in glucose homeostasis. Diabetic cardiomyopathy is characterised by cardiac hypertrophy and fibrosis. However, the underlying mechanisms of diabetic cardiomyopathy are not fully understood. This study aimed to investigate the effects of alpha-lipoic acid (ALA) on cardiac energy metabolism, antioxidant effect, and fibrosis in the hearts of Otsuka Long-Evans Tokushima fatty (OLETF) rats.MethodsAnimals were separated into non-diabetic Long-Evans Tokushima Otsuka (LETO) rats and diabetes-prone OLETF rats with or without ALA (200 mg/kg/day) administration for 16 weeks. Diabetic cardiomyopathy was assessed by staining with Sirius Red. The effect of ALA on AMPK signalling, antioxidant enzymes, and fibrosis-related genes in the heart of OLETF rats were performed by Western blot analysis or immunohistochemistry.ResultsWestern blot analysis showed that cardiac adenosine monophosphate-activated kinase (AMPK) signalling was lower in OLETF rats than in LETO rats, and that ALA treatment increased the signalling in OLETF rats. Furthermore, the low antioxidant activity in OLETF rats was increased by ALA treatment. In addition to increased Sirius red staining of collagen deposits, transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF) were expressed at higher levels in OLETF rat hearts than in LETO rat hearts, and the levels of these factors were decreased by ALA.ConclusionsALA enhances AMPK signalling, antioxidant, and antifibrogenic effect. Theses findings suggest that ALA may have beneficial effects in the treatment of diabetic cardiomyopathy.

Highlights

Hyperglycemia leads to cardiac oxidative stress and an imbalance in glucose homeostasis
alpha-lipoic acid (ALA) caused a significant reduction in the body weight of Otsuka Long-Evans Tokushima fatty (OLETF) rats (p < 0.05)
Whole heart weights were measured at the time of sacrifice, and the heart/body weight ratio was calculated for each group

Summary

Introduction

Hyperglycemia leads to cardiac oxidative stress and an imbalance in glucose homeostasis. Diabetic cardiomyopathy is characterised by cardiac hypertrophy and fibrosis. This study aimed to investigate the effects of alpha-lipoic acid (ALA) on cardiac energy metabolism, antioxidant effect, and fibrosis in the hearts of Otsuka Long-Evans Tokushima fatty (OLETF) rats. Despite the known relationship between energy metabolism and insulin resistance in the diabetic heart, the mechanism underlying the development of diabetic cardiomyopathy remains to be elucidated. Hypoadiponectinemia leads to cardiac oxidative stress and dysregulation of glucose homeostasis [5]. Adiponectin in insulin resistance correlates with activation of the adenosine monophosphate-activated kinase (AMPK) signalling pathway, which is implicated in fatty acid oxidation and glucose uptake. In adiponectin-deficient mice, diminished AMPK signalling in the heart is associated with increased cardiac hypertrophy [9]

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