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Int J Biol Sci 2017; 13(2):135-144. doi:10.7150/ijbs.17758

Research Paper

Lipocalin-2 Promotes Endoplasmic Reticulum Stress and Proliferation by Augmenting Intracellular Iron in Human Pulmonary Arterial Smooth Muscle Cells

Guoliang Wang1,2, Shenghua Liu1, Li Wang1, Liukun Meng1, Chuanjue Cui1, Hao Zhang1, Shengshou Hu1, Ning Ma2✉, Yingjie Wei1✉

1. State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
2. Beijing Children's Hospital, Capital Medical University, Beijing, China.

Abstract

Endoplasmic reticulum (ER) stress, a feature of many conditions associated with pulmonary hypertension (PH), is increasingly recognized as a common response to promote proliferation in the walls of pulmonary arteries. Increased expression of Lipocalin-2 in PH led us to test the hypothesis that Lipocalin-2, a protein known to sequester iron and regulate it intracellularly, might facilitate the ER stress and proliferation in pulmonary arterial smooth muscle cells (PASMCs). In this study, we observed greatly increased Lcn2 expression accompanied with increased ATF6 cleavage in a standard rat model of pulmonary hypertension induced by monocrotaline. In cultured human PASMCs, Lcn2 significantly promoted ER stress (determined by augmented cleavage and nuclear localization of ATF6, up-regulated transcription of GRP78 and NOGO, increased expression of SOD2, and mild augmented mitochondrial membrane potential) and proliferation (assessed by Ki67 staining and BrdU incorporation). Lcn2 promoted ER stress accompanied with augmented intracellular iron levels in human PASMCs. Treatment human PASMCs with FeSO4 induced the similar ER stress and proliferation response and iron chelator (deferoxamine) abrogated the ER stress and proliferation induced by Lcn2 in cultured human PASMCs. In conclusion, Lcn2 significantly promoted human PASMC ER stress and proliferation by augmenting intracellular iron. The up-regulation of Lcn2 probably involved in the pathogenesis and progression of PH.

Keywords: Lipocalin-2 (Lcn2), proliferation, endoplasmic reticulum stress, Iron, pulmonary hypertension.

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How to cite this article:
Wang G, Liu S, Wang L, Meng L, Cui C, Zhang H, Hu S, Ma N, Wei Y. Lipocalin-2 Promotes Endoplasmic Reticulum Stress and Proliferation by Augmenting Intracellular Iron in Human Pulmonary Arterial Smooth Muscle Cells. Int J Biol Sci 2017; 13(2):135-144. doi:10.7150/ijbs.17758. Available from http://www.ijbs.com/v13p0135.htm