PFKFB3 in Smooth Muscle Promotes Vascular Remodeling in Pulmonary Arterial Hypertension

American Journal of Respiratory and Critical Care Medicine
Laszlo KovacsYunchao Su

Abstract

Rationale: Glycolytic shift is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). It remains unknown how glycolysis is increased and how increased glycolysis contributes to pulmonary vascular remodeling in PAH.Objectives: To determine whether increased glycolysis is caused by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and how PFKFB3-driven glycolysis induces vascular remodeling in PAH.Methods: PFKFB3 levels were measured in pulmonary arteries of patients and animals with PAH. Lactate levels were assessed in lungs of animals with PAH and in pulmonary artery smooth muscle cells (PASMCs). Genetic and pharmacologic approaches were used to investigate the role of PFKFB3 in PAH.Measurements and Main Results: Lactate production was elevated in lungs of PAH rodents and in platelet-derived growth factor-treated PASMCs. PFKFB3 protein was higher in pulmonary arteries of patients and rodents with PAH, in PASMCs of patients with PAH, and in platelet-derived growth factor-treated PASMCs. PFKFB3 inhibition by genetic disruption and chemical inhibitor attenuated phosphorylation/activation of extracellular signal-regulated kinase (ERK1/2) and calpain-2, and vascular remodeling in PAH rodent models, an...Continue Reading

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Citations

Apr 21, 2020·American Journal of Respiratory and Critical Care Medicine·Elena A GoncharovaMark T Gladwin
Aug 9, 2020·American Journal of Physiology. Heart and Circulatory Physiology·Jia ShiFan He
Mar 9, 2019·American Journal of Respiratory and Critical Care Medicine·Sebastien Bonnet, Roxane Paulin
May 10, 2020·Journal of Cellular Physiology·Li-Huang ZhaZai-Xin Yu
Jul 19, 2020·Current Medical Science·Xiao-Fan Shi, Yun-Chao Su
Aug 28, 2020·International Journal of Hypertension·Shixin HeZhenfei Fang
Jun 20, 2019·Proceedings of the National Academy of Sciences of the United States of America·Yapeng CaoYuqing Huo
Jan 10, 2020·American Journal of Respiratory and Critical Care Medicine·Yuhu HeYing Yu
Dec 2, 2020·American Journal of Respiratory Cell and Molecular Biology·Tanmaye Nallan ChakravarthulaNathan J Alves
Oct 20, 2020·American Journal of Respiratory Cell and Molecular Biology·Huachun CuiGang Liu
Mar 30, 2021·Frontiers in Cell and Developmental Biology·Zi-Yi ZhouGuo-Rui Dou
Apr 5, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Anahita AbdaliStefano Bellosta
Jul 20, 2021·American Journal of Respiratory Cell and Molecular Biology·Yunchao SuLaszlo Kovacs

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Methods Mentioned

BETA
Confocal Microscopy
dissect

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