Ablation of endothelial Pfkfb3 protects mice from acute lung injury in LPS-induced endotoxemia

Lina Wang, Yapeng Cao, B. Gorshkov, Yaqi Zhou, Qiuhua Yang, Jiean Xu, Qian Ma, Xiaoyu Zhang, Jingjing Wang, Xiaoxiao Mao, Xianqiu Zeng, Yunchao Su, A. D. Verin, Mei Hong, Zhiping Liu, Yuqing Huo

Research output: Contribution to journalArticle

Abstract

Acute lung injury (ALI) is one of the leading causes of death in sepsis. Endothelial inflammation and dysfunction play a prominent role in development of ALI. Glycolysis is the predominant bioenergetic pathway for endothelial cells (ECs). However, the role of EC glycolysis in ALI of sepsis remains unclear. Here we show that both the expression and activity of PFKFB3, a key glycolytic activator, were markedly increased in lipopolysaccharide (LPS)-treated human pulmonary arterial ECs (HPAECs) in vitro and in lung ECs of mice challenged with LPS in vivo. PFKFB3 knockdown significantly reduced LPS-enhanced glycolysis in HPAECs. Compared with LPS-challenged wild-type mice, endothelial-specific Pfkfb3 knockout (Pfkfb3ΔVEC) mice exhibited reduced endothelium permeability, lower pulmonary edema, and higher survival rate. This was accompanied by decreased expression of intracellular adhesion molecule-1 (Icam-1) and vascular cell adhesion molecule 1 (Vcam-1), as well as decreased neutrophil and macrophage infiltration to the lung. Consistently, PFKFB3 silencing or PFKFB3 inhibition in HPAECs and human pulmonary microvascular ECs (HPMVECs) significantly downregulated LPS-induced expression of ICAM-1 and VCAM-1, and monocyte adhesion to human pulmonary ECs. In contrast, adenovirus-mediated PFKFB3 overexpression upregulated ICAM-1 and VCAM-1 expression in HPAECs. Mechanistically, PFKFB3 silencing suppressed LPS-induced nuclear translocation of nuclear factor κB (NF-κB)-p65, and NF-κB inhibitors abrogated PFKFB3-induced expression of ICAM-1 and VCAM-1. Finally, administration of the PFKFB3 inhibitor 3PO also reduced the inflammatory response of vascular endothelium and protected mice from LPS-induced ALI. Overall, these findings suggest that targeting PFKFB3-mediated EC glycolysis is an efficient therapeutic strategy for ALI in sepsis.

Original languageEnglish (US)
Article number104292
JournalPharmacological Research
Volume146
DOIs
StatePublished - Aug 1 2019
Externally publishedYes

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Endotoxemia
Acute Lung Injury
Lipopolysaccharides
Endothelial Cells
Lung
Vascular Cell Adhesion Molecule-1
Glycolysis
Intercellular Adhesion Molecule-1
Sepsis
Neutrophil Infiltration
Vascular Endothelium
Pulmonary Edema
Adenoviridae
Knockout Mice
Energy Metabolism
Endothelium
Monocytes
Cause of Death
Permeability
Down-Regulation

Keywords

  • 3PO (CID: 5720233)
  • Endothelial cell
  • Glycolysis
  • Inflammation
  • PFKFB3
  • Sepsis

ASJC Scopus subject areas

  • Pharmacology

Cite this

Ablation of endothelial Pfkfb3 protects mice from acute lung injury in LPS-induced endotoxemia. / Wang, Lina; Cao, Yapeng; Gorshkov, B.; Zhou, Yaqi; Yang, Qiuhua; Xu, Jiean; Ma, Qian; Zhang, Xiaoyu; Wang, Jingjing; Mao, Xiaoxiao; Zeng, Xianqiu; Su, Yunchao; Verin, A. D.; Hong, Mei; Liu, Zhiping; Huo, Yuqing.

In: Pharmacological Research, Vol. 146, 104292, 01.08.2019.

Research output: Contribution to journalArticle

Wang, L, Cao, Y, Gorshkov, B, Zhou, Y, Yang, Q, Xu, J, Ma, Q, Zhang, X, Wang, J, Mao, X, Zeng, X, Su, Y, Verin, AD, Hong, M, Liu, Z & Huo, Y 2019, 'Ablation of endothelial Pfkfb3 protects mice from acute lung injury in LPS-induced endotoxemia', Pharmacological Research, vol. 146, 104292. https://doi.org/10.1016/j.phrs.2019.104292
Wang, Lina ; Cao, Yapeng ; Gorshkov, B. ; Zhou, Yaqi ; Yang, Qiuhua ; Xu, Jiean ; Ma, Qian ; Zhang, Xiaoyu ; Wang, Jingjing ; Mao, Xiaoxiao ; Zeng, Xianqiu ; Su, Yunchao ; Verin, A. D. ; Hong, Mei ; Liu, Zhiping ; Huo, Yuqing. / Ablation of endothelial Pfkfb3 protects mice from acute lung injury in LPS-induced endotoxemia. In: Pharmacological Research. 2019 ; Vol. 146.
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abstract = "Acute lung injury (ALI) is one of the leading causes of death in sepsis. Endothelial inflammation and dysfunction play a prominent role in development of ALI. Glycolysis is the predominant bioenergetic pathway for endothelial cells (ECs). However, the role of EC glycolysis in ALI of sepsis remains unclear. Here we show that both the expression and activity of PFKFB3, a key glycolytic activator, were markedly increased in lipopolysaccharide (LPS)-treated human pulmonary arterial ECs (HPAECs) in vitro and in lung ECs of mice challenged with LPS in vivo. PFKFB3 knockdown significantly reduced LPS-enhanced glycolysis in HPAECs. Compared with LPS-challenged wild-type mice, endothelial-specific Pfkfb3 knockout (Pfkfb3ΔVEC) mice exhibited reduced endothelium permeability, lower pulmonary edema, and higher survival rate. This was accompanied by decreased expression of intracellular adhesion molecule-1 (Icam-1) and vascular cell adhesion molecule 1 (Vcam-1), as well as decreased neutrophil and macrophage infiltration to the lung. Consistently, PFKFB3 silencing or PFKFB3 inhibition in HPAECs and human pulmonary microvascular ECs (HPMVECs) significantly downregulated LPS-induced expression of ICAM-1 and VCAM-1, and monocyte adhesion to human pulmonary ECs. In contrast, adenovirus-mediated PFKFB3 overexpression upregulated ICAM-1 and VCAM-1 expression in HPAECs. Mechanistically, PFKFB3 silencing suppressed LPS-induced nuclear translocation of nuclear factor κB (NF-κB)-p65, and NF-κB inhibitors abrogated PFKFB3-induced expression of ICAM-1 and VCAM-1. Finally, administration of the PFKFB3 inhibitor 3PO also reduced the inflammatory response of vascular endothelium and protected mice from LPS-induced ALI. Overall, these findings suggest that targeting PFKFB3-mediated EC glycolysis is an efficient therapeutic strategy for ALI in sepsis.",
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AU - Zhou, Yaqi

AU - Yang, Qiuhua

AU - Xu, Jiean

AU - Ma, Qian

AU - Zhang, Xiaoyu

AU - Wang, Jingjing

AU - Mao, Xiaoxiao

AU - Zeng, Xianqiu

AU - Su, Yunchao

AU - Verin, A. D.

AU - Hong, Mei

AU - Liu, Zhiping

AU - Huo, Yuqing

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N2 - Acute lung injury (ALI) is one of the leading causes of death in sepsis. Endothelial inflammation and dysfunction play a prominent role in development of ALI. Glycolysis is the predominant bioenergetic pathway for endothelial cells (ECs). However, the role of EC glycolysis in ALI of sepsis remains unclear. Here we show that both the expression and activity of PFKFB3, a key glycolytic activator, were markedly increased in lipopolysaccharide (LPS)-treated human pulmonary arterial ECs (HPAECs) in vitro and in lung ECs of mice challenged with LPS in vivo. PFKFB3 knockdown significantly reduced LPS-enhanced glycolysis in HPAECs. Compared with LPS-challenged wild-type mice, endothelial-specific Pfkfb3 knockout (Pfkfb3ΔVEC) mice exhibited reduced endothelium permeability, lower pulmonary edema, and higher survival rate. This was accompanied by decreased expression of intracellular adhesion molecule-1 (Icam-1) and vascular cell adhesion molecule 1 (Vcam-1), as well as decreased neutrophil and macrophage infiltration to the lung. Consistently, PFKFB3 silencing or PFKFB3 inhibition in HPAECs and human pulmonary microvascular ECs (HPMVECs) significantly downregulated LPS-induced expression of ICAM-1 and VCAM-1, and monocyte adhesion to human pulmonary ECs. In contrast, adenovirus-mediated PFKFB3 overexpression upregulated ICAM-1 and VCAM-1 expression in HPAECs. Mechanistically, PFKFB3 silencing suppressed LPS-induced nuclear translocation of nuclear factor κB (NF-κB)-p65, and NF-κB inhibitors abrogated PFKFB3-induced expression of ICAM-1 and VCAM-1. Finally, administration of the PFKFB3 inhibitor 3PO also reduced the inflammatory response of vascular endothelium and protected mice from LPS-induced ALI. Overall, these findings suggest that targeting PFKFB3-mediated EC glycolysis is an efficient therapeutic strategy for ALI in sepsis.

AB - Acute lung injury (ALI) is one of the leading causes of death in sepsis. Endothelial inflammation and dysfunction play a prominent role in development of ALI. Glycolysis is the predominant bioenergetic pathway for endothelial cells (ECs). However, the role of EC glycolysis in ALI of sepsis remains unclear. Here we show that both the expression and activity of PFKFB3, a key glycolytic activator, were markedly increased in lipopolysaccharide (LPS)-treated human pulmonary arterial ECs (HPAECs) in vitro and in lung ECs of mice challenged with LPS in vivo. PFKFB3 knockdown significantly reduced LPS-enhanced glycolysis in HPAECs. Compared with LPS-challenged wild-type mice, endothelial-specific Pfkfb3 knockout (Pfkfb3ΔVEC) mice exhibited reduced endothelium permeability, lower pulmonary edema, and higher survival rate. This was accompanied by decreased expression of intracellular adhesion molecule-1 (Icam-1) and vascular cell adhesion molecule 1 (Vcam-1), as well as decreased neutrophil and macrophage infiltration to the lung. Consistently, PFKFB3 silencing or PFKFB3 inhibition in HPAECs and human pulmonary microvascular ECs (HPMVECs) significantly downregulated LPS-induced expression of ICAM-1 and VCAM-1, and monocyte adhesion to human pulmonary ECs. In contrast, adenovirus-mediated PFKFB3 overexpression upregulated ICAM-1 and VCAM-1 expression in HPAECs. Mechanistically, PFKFB3 silencing suppressed LPS-induced nuclear translocation of nuclear factor κB (NF-κB)-p65, and NF-κB inhibitors abrogated PFKFB3-induced expression of ICAM-1 and VCAM-1. Finally, administration of the PFKFB3 inhibitor 3PO also reduced the inflammatory response of vascular endothelium and protected mice from LPS-induced ALI. Overall, these findings suggest that targeting PFKFB3-mediated EC glycolysis is an efficient therapeutic strategy for ALI in sepsis.

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