PMID- 33300142 OWN - NLM STAT- MEDLINE DCOM- 20210705 LR - 20231024 IS - 1476-5381 (Electronic) IS - 0007-1188 (Linking) VI - 178 IP - 5 DP - 2021 Mar TI - Mice with a specific deficiency of Pfkfb3 in myeloid cells are protected from hypoxia-induced pulmonary hypertension. PG - 1055-1072 LID - 10.1111/bph.15339 [doi] AB - BACKGROUND AND PURPOSE: Macrophage infiltration into the lungs is a characteristic of pulmonary hypertension (PH). Glycolysis is the main metabolic pathway for macrophage activation. However, the effect of macrophage glycolysis on the development of PH remains unknown. We investigated the effect of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKBF3), a critical enzyme of macrophage glycolysis, on PH development. EXPERIMENTAL APPROACH: Lung tissues from PH patients were examined by immunostaining with macrophage markers. PH was induced in Wistar rats with SU5416/hypoxia and in mice with hypoxia. Lungs and macrophages were isolated for analysis by RT-PCR, western blot, flow cytometry, and immunostaining. KEY RESULTS: Expression of glycolytic molecules was increased in circulating peripheral blood mononuclear cells (PBMCs) and lung macrophages of PH patients. These results were also found in lung macrophages of SU5416/hypoxia (Su/Hx)-induced PH rats and hypoxia-induced PH mice. PH was ameliorated in myeloid-specific Pfkfb3-deficient mice (Pfkfb3(DeltaMvarphi) ) or mice treated with the PFKFB3 inhibitor 3PO, compared with their controls. Alveolar macrophages of PH Pfkfb3(DeltaMvarphi) mice produced lower levels of growth factors and pro-inflammatory cytokines than those of control mice. Circulating myeloid cells and lung myeloid cells were much fewer in PH Pfkfb3(DeltaMvarphi) mice than controls. Mechanistically, overexpression of Hif1a or Hif2a in bone marrow-derived macrophages (BMDMs) cultured with bone marrow of Pfkfb3(DeltaMvarphi) mice restored the decreased expression of pro-inflammatory cytokines and growth factors. CONCLUSIONS AND IMPLICATIONS: Myeloid Pfkfb3 deficiency protects mice from PH, thereby suggesting that myeloid PFKFB3 is one of the important targets in the therapeutic effect of PFKFB3 inhibition in PH treatment. CI - (c) 2020 The British Pharmacological Society. FAU - Wang, Lina AU - Wang L AD - State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China. AD - Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia, USA. FAU - Zhang, Xiaoyu AU - Zhang X AUID- ORCID: 0000-0002-7566-3445 AD - State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China. AD - Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia, USA. FAU - Cao, Yapeng AU - Cao Y AD - Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia, USA. FAU - Ma, Qian AU - Ma Q AD - Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia, USA. FAU - Mao, Xiaoxiao AU - Mao X AD - Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia, USA. FAU - Xu, Jiean AU - Xu J AD - Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia, USA. FAU - Yang, Qiuhua AU - Yang Q AD - Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia, USA. FAU - Zhou, Yaqi AU - Zhou Y AUID- ORCID: 0000-0003-0615-6631 AD - State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China. FAU - Lucas, Rudolf AU - Lucas R AUID- ORCID: 0000-0003-3805-8868 AD - Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia, USA. FAU - Fulton, David J AU - Fulton DJ AD - Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia, USA. FAU - Su, Yunchao AU - Su Y AD - Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA. FAU - Barman, Scott A AU - Barman SA AD - Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA. FAU - Hong, Mei AU - Hong M AD - State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China. FAU - Liu, Zhiping AU - Liu Z AD - State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China. AD - Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia, USA. FAU - Huo, Yuqing AU - Huo Y AD - Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia, USA. LA - eng GR - R01 EY030500/EY/NEI NIH HHS/United States GR - R01 HL134934/HL/NHLBI NIH HHS/United States GR - R01 HL142097/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20210201 PL - England TA - Br J Pharmacol JT - British journal of pharmacology JID - 7502536 RN - EC 2.7.1.105 (PFKFB3 protein, human) RN - EC 2.7.1.105 (PFKFB3 protein, mouse) RN - EC 2.7.1.105 (Phosphofructokinase-2) SB - IM MH - Animals MH - Glycolysis MH - Humans MH - *Hypertension, Pulmonary MH - Hypoxia MH - Leukocytes, Mononuclear/metabolism MH - Macrophages/metabolism MH - Mice MH - Phosphofructokinase-2/metabolism MH - Rats MH - Rats, Wistar OTO - NOTNLM OT - Hifs OT - PFKFB3 OT - glycolysis OT - macrophage OT - pulmonary hypertension EDAT- 2020/12/11 06:00 MHDA- 2021/07/06 06:00 CRDT- 2020/12/10 06:00 PHST- 2020/03/27 00:00 [received] PHST- 2020/11/09 00:00 [revised] PHST- 2020/11/23 00:00 [accepted] PHST- 2020/12/11 06:00 [pubmed] PHST- 2021/07/06 06:00 [medline] PHST- 2020/12/10 06:00 [entrez] AID - 10.1111/bph.15339 [doi] PST - ppublish SO - Br J Pharmacol. 2021 Mar;178(5):1055-1072. doi: 10.1111/bph.15339. Epub 2021 Feb 1.