Palmitic acid‑induced autophagy increases reactive oxygen species via the Ca2+/PKCα/NOX4 pathway and impairs endothelial function in human umbilical vein endothelial cells

Chen,Pan; Liu,Hengdao; Xiang,Hong; Zhou,Jianda; Zeng,Zhengpeng; Chen,Ruifang; Zhao,Shaoli; Xiao,Jie; Shu,Zhihao; Chen,Shuhua; Lu,Hongwei

doi:10.3892/etm.2019.7269

Palmitic acid‑induced autophagy increases reactive oxygen species via the Ca2+/PKCα/NOX4 pathway and impairs endothelial function in human umbilical vein endothelial cells

Authors:
- Pan Chen
- Hengdao Liu
- Hong Xiang
- Jianda Zhou
- Zhengpeng Zeng
- Ruifang Chen
- Shaoli Zhao
- Jie Xiao
- Zhihao Shu
- Shuhua Chen
- Hongwei Lu
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Affiliations: Center for Experimental Medical Research, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China, Department of Cardiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China, Department of Burns, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China, Department of Respiratory Medicine, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
Published online on: February 13, 2019 https://doi.org/10.3892/etm.2019.7269
Pages: 2425-2432
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

It is well known that the lipotoxic mechanism of palmitic acid (PA), a main constituent of triglyceride, is dependent on reactive oxygen species (ROS). Recently, it has also been reported that PA is an autophagy inducer. However, the causal association and underlying mechanism of induced autophagy and ROS in PA toxicity remain unclear. The present study demonstrates for the first time that PA‑induced autophagy enhances ROS generation via activating the calcium ion/protein kinase Cα/nicotinamide adenine dinucleotide phosphate oxidase 4 (Ca2+/PKCα/NOX4) pathway in human umbilical vein endothelial cells (HUVECs). It was revealed that PA treatment resulted in a significant increase in ROS generation and autophagic activity, leading to endothelial dysfunction as indicated by downregulated nitric oxide synthesis, decreased capillary‑like structure formation and damaged cell repair capability. Furthermore, PA effectively activated the Ca2+/PKCα/NOX4 pathway, which is indicative of upregulated cytosolic Ca2+ levels, activated PKCα and increased NOX4 protein expression. 3‑Methyladenine was then used to inhibit autophagy, which significantly reduced PA‑induced ROS generation and blocked the Ca2+/PKCα/NOX4 pathway. The endothelial dysfunction caused by PA was ameliorated by downregulating ROS generation using a NOX4 inhibitor. In conclusion, PA‑induced autophagy contributes to endothelial dysfunction by increasing oxidative stress via the Ca2+/PKCα/NOX4 pathway in HUVECs.

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