Heme Oxygenase-1 Prevents Cardiac Dysfunction in Streptozotocin-Diabetic Mice by Reducing Inflammation, Oxidative Stress, Apoptosis and Enhancing Autophagy

Yanli Zhao,Xu Gao,Lina Zhang,Guodong Wu,Yahui Peng,Jihong Li,Lujing Wang,Lingyun Zhou,Xingli Dong,Lining Si,Xiaoling Zhou,Xueying Zhang,Lei Zhang,Yu Qiao,Hui Huang,Wei Wang,Mengwei Zang

doi:10.1371/journal.pone.0075927

Abstract

Heme oxygenase-1 (HO-1) has been implicated in cardiac dysfunction, oxidative stress, inflammation, apoptosis and autophagy associated with heart failure, and atherosclerosis, in addition to its recognized role in metabolic syndrome and diabetes. Numerous studies have presented contradictory findings about the role of HO-1 in diabetic cardiomyopathy (DCM). In this study, we explored the role of HO-1 in myocardial dysfunction, myofibril structure, oxidative stress, inflammation, apoptosis and autophagy using a streptozotocin (STZ)-induced diabetes model in mice systemically overexpressing HO-1 (Tg-HO-1) or mutant HO-1 (Tg-mutHO-1). The diabetic mouse model was induced by multiple peritoneal injections of STZ. Two months after injection, left ventricular (LV) function was measured by echocardiography. In addition, molecular biomarkers related to oxidative stress, inflammation, apoptosis and autophagy were evaluated using classical molecular biological/biochemical techniques. Mice with DCM exhibited severe LV dysfunction, myofibril structure disarray, aberrant cardiac oxidative stress, inflammation, apoptosis, autophagy and increased levels of HO-1. In addition, we determined that systemic overexpression of HO-1 ameliorated left ventricular dysfunction, myofibril structure disarray, oxidative stress, inflammation, apoptosis and autophagy in DCM mice. Furthermore, serine/threonine-specific protein kinase (Akt) and AMP-activated protein kinase (AMPK) phosphorylation is normally inhibited in DCM, but overexpression of the HO-1 gene restored the phosphorylation of these kinases to normal levels. In contrast, the functions of HO-1 in DCM were significantly reversed by overexpression of mutant HO-1. This study underlines the unique roles of HO-1, including the inhibition of oxidative stress, inflammation and apoptosis and the enhancement of autophagy, in the pathogenesis of DCM.

Highlights

The epidemic of obesity and a sedentary lifestyle is projected to result in over 300 million people with diabetes mellitus by 2025 [1]
The results indicate that Heme oxygenase-1 (HO-1) activation is beneficial in preventing cardiac dysfunction and myofibril structure disarray by reducing cardiac oxidative stress, inflammation and apoptosis and enhancing cardiac autophagy
The injection of STZ induced moderate to severe hyperglycemic in three mouse genotypes including Tg-Heme oxygenase (HO)-1, Tg-mutHO-1 and Wt mice, whereas the blood glucose in

Summary

Introduction

The epidemic of obesity and a sedentary lifestyle is projected to result in over 300 million people with diabetes mellitus by 2025 [1]. Whereas HO-1 is normally expressed at a low level in most tissues except for the spleen, it is highly inducible in response to a variety of stimuli (such as hydrogen peroxide, UV irradiation, endotoxins, and hypoxia) to protect cells against oxidative and inflammatory injury [23]. It was reported that HO-1 induction under hyperglycemic conditions may lead to oxidative DNA and protein damage in human umbilical vein endothelial cells (HUVECs) [27]. Another group has shown that diabetesinduced oxidative stress in the heart is in part due to increased HO-1 expression and activity, which may be mediated by an increased level of redox-active iron [28]. The role of HO-1 in the cardiovascular complications of diabetes is still uncertain

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Discussion

Conclusion