PFKFB3 in smooth muscle promotes vascular remodeling in pulmonary arterial hypertension

Laszlo Kovacs, Yapeng Cao, Weihong Han, Louise Meadows, Anita Kovacs-Kasa, Dmitry Kondrikov, Alexander D. Verin, Scott A. Barman, Zheng Dong, Yuqing Huo, Yunchao Su

Research output: Contribution to journalArticle

10 Scopus citations

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, 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 lactateinduced 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.

Original languageEnglish (US)
Pages (from-to)617-627
Number of pages11
JournalAmerican journal of respiratory and critical care medicine
Volume200
Issue number5
DOIs
StatePublished - Sep 1 2019

Keywords

  • Calpain
  • Extracellular signal-regulated kinase
  • Glycolysis
  • Platelet-derived growth factor
  • Vascular smooth muscle

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Fingerprint Dive into the research topics of 'PFKFB3 in smooth muscle promotes vascular remodeling in pulmonary arterial hypertension'. Together they form a unique fingerprint.

  • Cite this