Hypoxia-mediated impaired erythrocyte Lands’ Cycle is pathogenic for sickle cell disease

Although Lands’ cycle was discovered in 1958, its function and cellular regulation in membrane homeostasis under physiological and pathological conditions remain largely unknown. Nonbiased high throughput metabolomic profiling revealed that Lands’ cycle was impaired leading to significantly elevated...

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Main Authors:	Wu, Hongyu, Bogdanov, Mikhail, Zhang, Yujin, Sun, Kaiqi, Zhao, Shushan, Song, Anren, Luo, Renna, Parchim, Nicholas F., Liu, Hong, Huang, Aji, Adebiyi, Morayo G., Jin, Jianping, Alexander, Danny C., Milburn, Michael V., Idowu, Modupe, Juneja, Harinder S., Kellems, Rodney E., Dowhan, William, Xia, Yang
Format:	Online
Language:	English
Published:	Nature Publishing Group 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4951653/

id	pubmed-4951653
recordtype	oai_dc
spelling	pubmed-49516532016-07-26 Hypoxia-mediated impaired erythrocyte Lands’ Cycle is pathogenic for sickle cell disease Wu, Hongyu Bogdanov, Mikhail Zhang, Yujin Sun, Kaiqi Zhao, Shushan Song, Anren Luo, Renna Parchim, Nicholas F. Liu, Hong Huang, Aji Adebiyi, Morayo G. Jin, Jianping Alexander, Danny C. Milburn, Michael V. Idowu, Modupe Juneja, Harinder S. Kellems, Rodney E. Dowhan, William Xia, Yang Article Although Lands’ cycle was discovered in 1958, its function and cellular regulation in membrane homeostasis under physiological and pathological conditions remain largely unknown. Nonbiased high throughput metabolomic profiling revealed that Lands’ cycle was impaired leading to significantly elevated erythrocyte membrane lysophosphatidylcholine (LysoPC) content and circulating and erythrocyte arachidonic acid (AA) in mice with sickle cell disease (SCD), a prevalent hemolytic genetic disorder. Correcting imbalanced Lands’ cycle by knockdown of phospholipase 2 (cPLA2) or overexpression of lysophosphatidycholine acyltransferase 1 (LPCAT1), two key enzymes of Lands’ cycle in hematopoietic stem cells, reduced elevated erythrocyte membrane LysoPC content and circulating AA levels and attenuated sickling, inflammation and tissue damage in SCD chimeras. Human translational studies validated SCD mouse findings and further demonstrated that imbalanced Lands’ cycle induced LysoPC production directly promotes sickling in cultured mouse and human SCD erythrocytes. Mechanistically, we revealed that hypoxia-mediated ERK activation underlies imbalanced Lands’ cycle by preferentially inducing the activity of PLA2 but not LPCAT in human and mouse SCD erythrocytes. Overall, our studies have identified a pathological role of imbalanced Lands’ cycle in SCD erythrocytes, novel molecular basis regulating Lands’ cycle and therapeutic opportunities for the disease. Nature Publishing Group 2016-07-20 /pmc/articles/PMC4951653/ /pubmed/27436223 http://dx.doi.org/10.1038/srep29637 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Wu, Hongyu Bogdanov, Mikhail Zhang, Yujin Sun, Kaiqi Zhao, Shushan Song, Anren Luo, Renna Parchim, Nicholas F. Liu, Hong Huang, Aji Adebiyi, Morayo G. Jin, Jianping Alexander, Danny C. Milburn, Michael V. Idowu, Modupe Juneja, Harinder S. Kellems, Rodney E. Dowhan, William Xia, Yang
spellingShingle	Wu, Hongyu Bogdanov, Mikhail Zhang, Yujin Sun, Kaiqi Zhao, Shushan Song, Anren Luo, Renna Parchim, Nicholas F. Liu, Hong Huang, Aji Adebiyi, Morayo G. Jin, Jianping Alexander, Danny C. Milburn, Michael V. Idowu, Modupe Juneja, Harinder S. Kellems, Rodney E. Dowhan, William Xia, Yang Hypoxia-mediated impaired erythrocyte Lands’ Cycle is pathogenic for sickle cell disease
author_facet	Wu, Hongyu Bogdanov, Mikhail Zhang, Yujin Sun, Kaiqi Zhao, Shushan Song, Anren Luo, Renna Parchim, Nicholas F. Liu, Hong Huang, Aji Adebiyi, Morayo G. Jin, Jianping Alexander, Danny C. Milburn, Michael V. Idowu, Modupe Juneja, Harinder S. Kellems, Rodney E. Dowhan, William Xia, Yang
author_sort	Wu, Hongyu
title	Hypoxia-mediated impaired erythrocyte Lands’ Cycle is pathogenic for sickle cell disease
title_short	Hypoxia-mediated impaired erythrocyte Lands’ Cycle is pathogenic for sickle cell disease
title_full	Hypoxia-mediated impaired erythrocyte Lands’ Cycle is pathogenic for sickle cell disease
title_fullStr	Hypoxia-mediated impaired erythrocyte Lands’ Cycle is pathogenic for sickle cell disease
title_full_unstemmed	Hypoxia-mediated impaired erythrocyte Lands’ Cycle is pathogenic for sickle cell disease
title_sort	hypoxia-mediated impaired erythrocyte lands’ cycle is pathogenic for sickle cell disease
description	Although Lands’ cycle was discovered in 1958, its function and cellular regulation in membrane homeostasis under physiological and pathological conditions remain largely unknown. Nonbiased high throughput metabolomic profiling revealed that Lands’ cycle was impaired leading to significantly elevated erythrocyte membrane lysophosphatidylcholine (LysoPC) content and circulating and erythrocyte arachidonic acid (AA) in mice with sickle cell disease (SCD), a prevalent hemolytic genetic disorder. Correcting imbalanced Lands’ cycle by knockdown of phospholipase 2 (cPLA2) or overexpression of lysophosphatidycholine acyltransferase 1 (LPCAT1), two key enzymes of Lands’ cycle in hematopoietic stem cells, reduced elevated erythrocyte membrane LysoPC content and circulating AA levels and attenuated sickling, inflammation and tissue damage in SCD chimeras. Human translational studies validated SCD mouse findings and further demonstrated that imbalanced Lands’ cycle induced LysoPC production directly promotes sickling in cultured mouse and human SCD erythrocytes. Mechanistically, we revealed that hypoxia-mediated ERK activation underlies imbalanced Lands’ cycle by preferentially inducing the activity of PLA2 but not LPCAT in human and mouse SCD erythrocytes. Overall, our studies have identified a pathological role of imbalanced Lands’ cycle in SCD erythrocytes, novel molecular basis regulating Lands’ cycle and therapeutic opportunities for the disease.
publisher	Nature Publishing Group
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4951653/
_version_	1613612208525148160

Hypoxia-mediated impaired erythrocyte Lands’ Cycle is pathogenic for sickle cell disease

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