Involvement of Kv1.5 Protein in Oxidative Vascular Endothelial Cell Injury

Wen-Liang Chen,Jie Liu,Guan-Lei Wang,Yong-Yuan Guan,Ying Xiao,Jie Li,Xiong-Qing Huang,Yun-Ying Huang,Li-Yan Zhao,Jian-Wen Chen

doi:10.1371/journal.pone.0049758

Abstract

Endothelial injury related to oxidative stress is a key event in cardiovascular diseases, such as hypertension and atherosclerosis. The activation of the redox-sensitive Kv1.5 potassium channel mediates mitochondrial reactive oxygen species (ROS)-induced apoptosis in vascular smooth muscle cells and some cancer cells. Kv1.5 channel is therefore taken as a new potential therapeutic target for pulmonary hypertension and cancers. Although Kv1.5 is abundantly expressed in vascular endothelium, there is little knowledge of its role in endothelial injury related to oxidative stress. We found that DPO-1, a specific inhibitor of Kv1.5, attenuated H2O2-evoked endothelial cell apoptosis in an in vivo rat carotid arterial model. In human umbilical vein endothelial cells (HUVECs) and human pulmonary arterial endothelial cells (HPAECs), angiotensin II and oxLDL time- or concentration-dependently enhanced Kv1.5 protein expression in parallel with the production of intracellular ROS and endothelial cell injury. Moreover, siRNA-mediated knockdown of Kv1.5 attenuated, whereas adenovirus-mediated Kv1.5 cDNA overexpression enhanced oxLDL–induced cellular damage, NADPH oxidase and mitochondria-derived ROS production and restored the decrease in protein expression of mitochondria uncoupling protein 2 (UCP2). Collectively, these data suggest that Kv1.5 may play an important role in oxidative vascular endothelial injury.

Highlights

Intact endothelium is important in the regulation of cardiovascular cell growth, cell migration, proliferation and apoptosis and vascular tone
We found that DPO-1, a specific Kv1.5 inhibitor could significantly reduce apoptotic endothelial cells in an in vivo H2O2-induced carotid arterial EC injury group (H2O2) -induced endothelial injury model
In oxidized low density lipoprotein (oxLDL)-induced endothelial cell injury model, we further found that knockdown of KCNA5 gene attenuated, whereas overexpression of KCNA5 gene enhanced oxLDL-induced endothelial morphological changes, reactive oxygen species (ROS) generation derived from NADPH oxidase and mitochondria, and the protein expression of uncoupling protein 2 (UCP2), a modulator of mitochondria-derived ROS production [19,20]

Summary

Introduction

Intact endothelium is important in the regulation of cardiovascular cell growth, cell migration, proliferation and apoptosis and vascular tone. Large evidence has shown that chronic or acute reactive oxygen species (ROS) overproduction plays the critical role in endothelial insult and subsequent initiation of vascular remodeling [1]. Various cardiovascular stimuli, such as angiotensin II (Ang II) and oxidized low density lipoprotein (oxLDL) can trigger endothelial injury, which is accompanied by the increase in ROS production [1,2,3,4]. ROS can modulate signaling pathways in endothelial cells at multiple levels, such as membrane receptors, channels, kinases and nuclear transcription factors, the precise mechanism underlying endothelial apoptosis related to oxidative stress is still not clear

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