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PFKFB3 in Smooth Muscle Promotes Vascular Remodeling in Pulmonary Arterial Hypertension.
American Journal of Respiratory and Critical Care Medicine 2019 Februrary 29
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 PAH patients and animals. Lactate levels were assessed in lungs of PAH animals and in pulmonary artery smooth muscle cells (PASMCs). Genetic and pharmacological 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 (PDGF)-treated PASMCs. PFKFB3 protein was higher in pulmonary arteries of PAH patients and rodents, in PASMCs of PAH patients and in PDGF-treated PASMCs. PFKFB3 inhibition by genetic disruption and chemical inhibitor attenuated phosphorylation/activation of ERK1/2 and calpain-2, and vascular remodeling in PAH rodent models, and reduced PDGF-induced phosphorylation/activation of ERK1/2 and calpain-2, collagen synthesis and proliferation of PASMCs. ERK1/2 inhibition attenuated phosphorylation/activation of calpain-2, and vascular remodeling in Sugen/Hypoxia PAH rats, and reduced lactate-induced phosphorylation/activation of calpain-2, collagen synthesis and proliferation of PASMCs. Calpain-2 inhibition reduced lactate-induced collagen synthesis and proliferation of PASMCs.
CONCLUSION: Upregulated PFKFB3 mediates collagen synthesis and proliferation of PASMCs, contributing to vascular remodeling in PAH. The mechanism is through the elevation of glycolysis and lactate that result in the activation of calpain by ERK1/2-dependent phosphorylation of calpain-2.
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 PAH patients and animals. Lactate levels were assessed in lungs of PAH animals and in pulmonary artery smooth muscle cells (PASMCs). Genetic and pharmacological 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 (PDGF)-treated PASMCs. PFKFB3 protein was higher in pulmonary arteries of PAH patients and rodents, in PASMCs of PAH patients and in PDGF-treated PASMCs. PFKFB3 inhibition by genetic disruption and chemical inhibitor attenuated phosphorylation/activation of ERK1/2 and calpain-2, and vascular remodeling in PAH rodent models, and reduced PDGF-induced phosphorylation/activation of ERK1/2 and calpain-2, collagen synthesis and proliferation of PASMCs. ERK1/2 inhibition attenuated phosphorylation/activation of calpain-2, and vascular remodeling in Sugen/Hypoxia PAH rats, and reduced lactate-induced phosphorylation/activation of calpain-2, collagen synthesis and proliferation of PASMCs. Calpain-2 inhibition reduced lactate-induced collagen synthesis and proliferation of PASMCs.
CONCLUSION: Upregulated PFKFB3 mediates collagen synthesis and proliferation of PASMCs, contributing to vascular remodeling in PAH. The mechanism is through the elevation of glycolysis and lactate that result in the activation of calpain by ERK1/2-dependent phosphorylation of calpain-2.
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