FoxO3a Modulates Hypoxia Stress Induced Oxidative Stress and Apoptosis in Cardiac Microvascular Endothelial Cells

Shenwei Zhang,Xiaolin Niu,Li Yu,Yilin Zhao,Yiqiang Yuan,Ming Xu,Qiangsun Zheng,Jianghong Chen,Yujie Zhao

doi:10.1371/journal.pone.0080342

Shenwei Zhang, Xiaolin Niu + Show 7 more

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https://doi.org/10.1371/journal.pone.0080342

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Cardiac microvascular endothelial cells (CMECs) dysfunction induced by hypoxia is an important pathophysiological event in myocardium ischemic injury, whereas, the underlying mechanism is not fully clarified. FoxO transcription factors regulate target genes involved in apoptosis and cellular reactive oxygen species (ROS) production. Therefore, the present study was designed to elucidate the potential role of FoxOs on the hypoxia-induced ROS formation and apoptosis in CMECs. Exposure to low oxygen tension stimulated ROS accumulation and increased apoptosis in CMECs within 6–24 h. Hypoxia also significantly increased the expressions of HIF-1α and FoxO3a. However, hypoxia decreased the phosphorylation of Akt and FoxO3a, correlated with increased nuclear accumulation. Conversely, the expression of FoxO1 was not significantly altered by hypoxia. After inhibition of HIF-1α by siRNA, we observed that hypoxia-induced ROS accumulation and apoptosis of CMECs were decreased. Meanwhile, knockdown of HIF-1α also inhibited hypoxia induced FoxO3a expression in CMECs, but did not affect FoxO1 expression. Furthermore, hypoxia-induced ROS formation and apoptosis in CMECs were correlated with the disturbance of Bcl-2 family proteins, which were abolished by FoxO3a silencing with siRNA. In conclusion, our data provide evidence that FoxO3a leads to ROS accumulation in CMECs, and in parallel, induces the disturbance of Bcl-2 family proteins which results in apoptosis.

Highlights

Despite a wide range of therapeutic approaches, myocardial infarction (MI) continues to be a major cause of significant morbidity and mortality worldwide[1]
It is well recognized that Cardiac microvascular endothelial cells (CMECs) apoptosis induced by hypoxia injury is an important pathophysiological event in myocardium ischemic injury[2]
We demonstrate for the first time that HIF-1a and FoxO3a play the central role in hypoxic injury of CMECs

Summary

Introduction

Despite a wide range of therapeutic approaches, myocardial infarction (MI) continues to be a major cause of significant morbidity and mortality worldwide[1]. Coronary microcirculation dysfunction is a primary etiological component of myocardium ischemic injury. Cardiac microvascular endothelial cells (CMECs), comprising up to one-third of the total heart cells, play a critical role to keep coronary microvessels (diameter,150 mm) and adjacent cardiomyocytes in normal condition[2]. Previous evidences suggest that CMECs malfunction and apoptosis induced by hypoxia injury precedes cardiomyocyte apoptosis[3]. The mechanism of CMECs dysfunction induced by hypoxia injury is still not clear. Oxidative stress, which is associated with increased formation of reactive oxygen species (ROS), contributes to the pathophysiology of hypoxia injury[4,5]. Increased ROS accumulation leads to proteins, nucleic acids and intracellular membranes modifications, subsequently inducing impairing cellular functions[6]. Understanding the intracellular mechanism that regulates ROS formation is important to protect CMECs from hypoxic injury

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