PFKFB3 in Smooth Muscle Promotes Vascular Remodeling in Pulmonary Arterial Hypertension
| Autor: | Yuqing Huo, Louise Meadows, Weihong Han, Scott A. Barman, Alexander D. Verin, Yunchao Su, Anita Kovacs-Kasa, Laszlo Kovacs, Dmitry Kondrikov, Yapeng Cao, Zheng Dong |
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| Rok vydání: | 2019 |
| Předmět: |
Pulmonary and Respiratory Medicine
medicine.medical_specialty Platelet-derived growth factor Vascular smooth muscle Critical Care and Intensive Care Medicine 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine.artery Internal medicine Medicine Glycolysis 030212 general & internal medicine biology Kinase business.industry Calpain Hypoxia (medical) Endocrinology 030228 respiratory system chemistry Pulmonary artery biology.protein Phosphorylation medicine.symptom business |
| Zdroj: | American Journal of Respiratory and Critical Care Medicine. 200:617-627 |
| ISSN: | 1535-4970 1073-449X |
| DOI: | 10.1164/rccm.201812-2290oc |
| Popis: | 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, and reduced platelet-derived growth factor-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.Conclusions: 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 results in the activation of calpain by ERK1/2-dependent phosphorylation of calpain-2. |
| Databáze: | OpenAIRE |
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