PFKFB3-mediated endothelial glycolysis promotes pulmonary hypertension

Yapeng Cao, Xiaoyu Zhang, Lina Wang, Qiuhua Yang, Qian Ma, Jiean Xu, Jingjing Wang, Laszlo Kovacs, Ramon J. Ayon, Zhiping Liu, Min Zhang, Yaqi Zhou, Xianqiu Zeng, Yiming Xu, Yong Wang, David J Fulton, Neal L. Weintraub, Rudolf Lucas, Zheng Dong, Jason X.J. YuanJennifer C Sullivan, Louise Meadows, Scott A. Barman, Chaodong Wu, Junmin Quan, Mei Hong, Yunchao Su, Yuqing Huo

Research output: Contribution to journalArticle

Abstract

Increased glycolysis in the lung vasculature has been connected to the development of pulmonary hypertension (PH). We therefore investigated whether glycolytic regulator 6-phosphofructo-2-kinase/ fructose-2, 6-bisphosphatase (PFKFB3)-mediated endothelial glycolysis plays a critical role in the development of PH. Heterozygous global deficiency of Pfkfb3 protected mice from developing hypoxia-induced PH, and administration of the PFKFB3 inhibitor 3PO almost completely prevented PH in rats treated with Sugen 5416/hypoxia, indicating a causative role of PFKFB3 in the development of PH. Immunostaining of lung sections and Western blot with isolated lung endothelial cells showed a dramatic increase in PFKFB3 expression and activity in pulmonary endothelial cells of rodents and humans with PH. We generated mice that were constitutively or inducibly deficient in endothelial Pfkfb3 and found that these mice were incapable of developing PH or showed slowed PH progression. Compared with control mice, endothelial Pfkfb3-knockout mice exhibited less severity of vascular smooth muscle cell proliferation, endothelial inflammation, and leukocyte recruitment in the lungs. In the absence of PFKFB3, lung endothelial cells from rodents and humans with PH produced lower levels of growth factors (such as PDGFB and FGF2) and proinflammatory factors (such as CXCL12 and IL1β). This is mechanistically linked to decreased levels of HIF2A in lung ECs following PFKFB3 knockdown. Taken together, these results suggest that targeting PFKFB3 is a promising strategy for the treatment of PH.

Original languageEnglish (US)
Pages (from-to)13394-13403
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number27
DOIs
StatePublished - Jan 1 2019

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Glycolysis
Pulmonary Hypertension
Lung
Endothelial Cells
Rodentia
Phosphofructokinase-2
Proto-Oncogene Proteins c-sis
Fibroblast Growth Factor 2
Vascular Smooth Muscle
Knockout Mice
Smooth Muscle Myocytes
Intercellular Signaling Peptides and Proteins
Leukocytes
Western Blotting
Cell Proliferation
Inflammation

Keywords

  • Endothelial cells
  • Glycolysis
  • Pulmonary hypertension

ASJC Scopus subject areas

  • General

Cite this

PFKFB3-mediated endothelial glycolysis promotes pulmonary hypertension. / Cao, Yapeng; Zhang, Xiaoyu; Wang, Lina; Yang, Qiuhua; Ma, Qian; Xu, Jiean; Wang, Jingjing; Kovacs, Laszlo; Ayon, Ramon J.; Liu, Zhiping; Zhang, Min; Zhou, Yaqi; Zeng, Xianqiu; Xu, Yiming; Wang, Yong; Fulton, David J; Weintraub, Neal L.; Lucas, Rudolf; Dong, Zheng; Yuan, Jason X.J.; Sullivan, Jennifer C; Meadows, Louise; Barman, Scott A.; Wu, Chaodong; Quan, Junmin; Hong, Mei; Su, Yunchao; Huo, Yuqing.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 27, 01.01.2019, p. 13394-13403.

Research output: Contribution to journalArticle

Cao, Y, Zhang, X, Wang, L, Yang, Q, Ma, Q, Xu, J, Wang, J, Kovacs, L, Ayon, RJ, Liu, Z, Zhang, M, Zhou, Y, Zeng, X, Xu, Y, Wang, Y, Fulton, DJ, Weintraub, NL, Lucas, R, Dong, Z, Yuan, JXJ, Sullivan, JC, Meadows, L, Barman, SA, Wu, C, Quan, J, Hong, M, Su, Y & Huo, Y 2019, 'PFKFB3-mediated endothelial glycolysis promotes pulmonary hypertension', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 27, pp. 13394-13403. https://doi.org/10.1073/pnas.1821401116
Cao, Yapeng ; Zhang, Xiaoyu ; Wang, Lina ; Yang, Qiuhua ; Ma, Qian ; Xu, Jiean ; Wang, Jingjing ; Kovacs, Laszlo ; Ayon, Ramon J. ; Liu, Zhiping ; Zhang, Min ; Zhou, Yaqi ; Zeng, Xianqiu ; Xu, Yiming ; Wang, Yong ; Fulton, David J ; Weintraub, Neal L. ; Lucas, Rudolf ; Dong, Zheng ; Yuan, Jason X.J. ; Sullivan, Jennifer C ; Meadows, Louise ; Barman, Scott A. ; Wu, Chaodong ; Quan, Junmin ; Hong, Mei ; Su, Yunchao ; Huo, Yuqing. / PFKFB3-mediated endothelial glycolysis promotes pulmonary hypertension. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 27. pp. 13394-13403.
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T1 - PFKFB3-mediated endothelial glycolysis promotes pulmonary hypertension

AU - Cao, Yapeng

AU - Zhang, Xiaoyu

AU - Wang, Lina

AU - Yang, Qiuhua

AU - Ma, Qian

AU - Xu, Jiean

AU - Wang, Jingjing

AU - Kovacs, Laszlo

AU - Ayon, Ramon J.

AU - Liu, Zhiping

AU - Zhang, Min

AU - Zhou, Yaqi

AU - Zeng, Xianqiu

AU - Xu, Yiming

AU - Wang, Yong

AU - Fulton, David J

AU - Weintraub, Neal L.

AU - Lucas, Rudolf

AU - Dong, Zheng

AU - Yuan, Jason X.J.

AU - Sullivan, Jennifer C

AU - Meadows, Louise

AU - Barman, Scott A.

AU - Wu, Chaodong

AU - Quan, Junmin

AU - Hong, Mei

AU - Su, Yunchao

AU - Huo, Yuqing

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N2 - Increased glycolysis in the lung vasculature has been connected to the development of pulmonary hypertension (PH). We therefore investigated whether glycolytic regulator 6-phosphofructo-2-kinase/ fructose-2, 6-bisphosphatase (PFKFB3)-mediated endothelial glycolysis plays a critical role in the development of PH. Heterozygous global deficiency of Pfkfb3 protected mice from developing hypoxia-induced PH, and administration of the PFKFB3 inhibitor 3PO almost completely prevented PH in rats treated with Sugen 5416/hypoxia, indicating a causative role of PFKFB3 in the development of PH. Immunostaining of lung sections and Western blot with isolated lung endothelial cells showed a dramatic increase in PFKFB3 expression and activity in pulmonary endothelial cells of rodents and humans with PH. We generated mice that were constitutively or inducibly deficient in endothelial Pfkfb3 and found that these mice were incapable of developing PH or showed slowed PH progression. Compared with control mice, endothelial Pfkfb3-knockout mice exhibited less severity of vascular smooth muscle cell proliferation, endothelial inflammation, and leukocyte recruitment in the lungs. In the absence of PFKFB3, lung endothelial cells from rodents and humans with PH produced lower levels of growth factors (such as PDGFB and FGF2) and proinflammatory factors (such as CXCL12 and IL1β). This is mechanistically linked to decreased levels of HIF2A in lung ECs following PFKFB3 knockdown. Taken together, these results suggest that targeting PFKFB3 is a promising strategy for the treatment of PH.

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KW - Glycolysis

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