Hedgehog interacting protein (HHIP) represses airway remodeling and metabolic reprogramming in COPD-derived airway smooth muscle cells

Abstract Although HHIP locus has been consistently associated with the susceptibility to COPD including airway remodeling and emphysema in genome-wide association studies, the molecular mechanism underlying this genetic association remains incompletely understood. By utilizing Hhip +/- mice and prim...

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Autores principales:	Yan Li, Li Zhang, Francesca Polverino, Feng Guo, Yuan Hao, Taotao Lao, Shuang Xu, Lijia Li, Betty Pham, Caroline A. Owen, Xiaobo Zhou
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7b317d5258654001bd69e0da4ad2fb95
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spelling	oai:doaj.org-article:7b317d5258654001bd69e0da4ad2fb952021-12-02T13:41:44ZHedgehog interacting protein (HHIP) represses airway remodeling and metabolic reprogramming in COPD-derived airway smooth muscle cells10.1038/s41598-021-88434-x2045-2322https://doaj.org/article/7b317d5258654001bd69e0da4ad2fb952021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88434-xhttps://doaj.org/toc/2045-2322Abstract Although HHIP locus has been consistently associated with the susceptibility to COPD including airway remodeling and emphysema in genome-wide association studies, the molecular mechanism underlying this genetic association remains incompletely understood. By utilizing Hhip +/- mice and primary human airway smooth muscle cells (ASMCs), here we aim to determine whether HHIP haploinsufficiency increases airway smooth muscle mass by reprogramming glucose metabolism, thus contributing to airway remodeling in COPD pathogenesis. The mRNA levels of HHIP were compared in normal and COPD-derived ASMCs. Mitochondrial oxygen consumption rate and lactate levels in the medium were measured in COPD-derived ASMCs with or without HHIP overexpression as readouts of glucose oxidative phosphorylation and aerobic glycolysis rates. The proliferation rate was measured in healthy and COPD-derived ASMCs treated with or without 2-DG. Smooth muscle mass around airways was measured by immunofluorescence staining for α-smooth muscle actin (α-SMA) in lung sections from Hhip +/- mice and their wild type littermates, Hhip +/+ mice. Airway remodeling was assessed in Hhip +/- and Hhip +/- mice exposed to 6 months of cigarette smoke. Our results show HHIP inhibited aerobic glycolysis and represses cell proliferation in COPD-derived ASMCs. Notably, knockdown of HHIP in normal ASMCs increased PKM2 activity. Importantly, Hhip +/- mice demonstrated increased airway remodeling and increased intensity of α-SMA staining around airways compared to Hhip +/+ mice. In conclusion, our findings suggest that HHIP represses aerobic glycolysis and ASMCs hyperplasia, which may contribute to the increased airway remodeling in Hhip +/- mice.Yan LiLi ZhangFrancesca PolverinoFeng GuoYuan HaoTaotao LaoShuang XuLijia LiBetty PhamCaroline A. OwenXiaobo ZhouNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yan Li Li Zhang Francesca Polverino Feng Guo Yuan Hao Taotao Lao Shuang Xu Lijia Li Betty Pham Caroline A. Owen Xiaobo Zhou Hedgehog interacting protein (HHIP) represses airway remodeling and metabolic reprogramming in COPD-derived airway smooth muscle cells
description	Abstract Although HHIP locus has been consistently associated with the susceptibility to COPD including airway remodeling and emphysema in genome-wide association studies, the molecular mechanism underlying this genetic association remains incompletely understood. By utilizing Hhip +/- mice and primary human airway smooth muscle cells (ASMCs), here we aim to determine whether HHIP haploinsufficiency increases airway smooth muscle mass by reprogramming glucose metabolism, thus contributing to airway remodeling in COPD pathogenesis. The mRNA levels of HHIP were compared in normal and COPD-derived ASMCs. Mitochondrial oxygen consumption rate and lactate levels in the medium were measured in COPD-derived ASMCs with or without HHIP overexpression as readouts of glucose oxidative phosphorylation and aerobic glycolysis rates. The proliferation rate was measured in healthy and COPD-derived ASMCs treated with or without 2-DG. Smooth muscle mass around airways was measured by immunofluorescence staining for α-smooth muscle actin (α-SMA) in lung sections from Hhip +/- mice and their wild type littermates, Hhip +/+ mice. Airway remodeling was assessed in Hhip +/- and Hhip +/- mice exposed to 6 months of cigarette smoke. Our results show HHIP inhibited aerobic glycolysis and represses cell proliferation in COPD-derived ASMCs. Notably, knockdown of HHIP in normal ASMCs increased PKM2 activity. Importantly, Hhip +/- mice demonstrated increased airway remodeling and increased intensity of α-SMA staining around airways compared to Hhip +/+ mice. In conclusion, our findings suggest that HHIP represses aerobic glycolysis and ASMCs hyperplasia, which may contribute to the increased airway remodeling in Hhip +/- mice.
format	article
author	Yan Li Li Zhang Francesca Polverino Feng Guo Yuan Hao Taotao Lao Shuang Xu Lijia Li Betty Pham Caroline A. Owen Xiaobo Zhou
author_facet	Yan Li Li Zhang Francesca Polverino Feng Guo Yuan Hao Taotao Lao Shuang Xu Lijia Li Betty Pham Caroline A. Owen Xiaobo Zhou
author_sort	Yan Li
title	Hedgehog interacting protein (HHIP) represses airway remodeling and metabolic reprogramming in COPD-derived airway smooth muscle cells
title_short	Hedgehog interacting protein (HHIP) represses airway remodeling and metabolic reprogramming in COPD-derived airway smooth muscle cells
title_full	Hedgehog interacting protein (HHIP) represses airway remodeling and metabolic reprogramming in COPD-derived airway smooth muscle cells
title_fullStr	Hedgehog interacting protein (HHIP) represses airway remodeling and metabolic reprogramming in COPD-derived airway smooth muscle cells
title_full_unstemmed	Hedgehog interacting protein (HHIP) represses airway remodeling and metabolic reprogramming in COPD-derived airway smooth muscle cells
title_sort	hedgehog interacting protein (hhip) represses airway remodeling and metabolic reprogramming in copd-derived airway smooth muscle cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/7b317d5258654001bd69e0da4ad2fb95
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Hedgehog interacting protein (HHIP) represses airway remodeling and metabolic reprogramming in COPD-derived airway smooth muscle cells

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