Inhibition of anaplerosis attenuated vascular proliferation in pulmonary arterial hypertension

Mathews Valuparampil Varghese, Joel James, Cody A. Eccles, Maki Niihori, Olga Rafikova, Ruslan Rafikov

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Vascular remodeling is considered a key event in the pathogenesis of pulmonary arterial hypertension (PAH). However, mechanisms of gaining the proliferative phenotype by pulmonary vascular cells are still unresolved. Due to well-established pyruvate dehydrogenase (PDH) deficiency in PAH pathogenesis, we hypothesized that the activation of another branch of pyruvate metabolism, anaplerosis, via pyruvate carboxylase (PC) could be a key contributor to the metabolic reprogramming of the vasculature. In sugen/hypoxic PAH rats, vascular proliferation was found to be accompanied by increased activation of Akt signaling, which upregulated membrane Glut4 translocation and caused upregulation of hexokinase and pyruvate kinase-2, and an overall increase in the glycolytic flux. Decreased PDH activity and upregulation of PC shuttled more pyruvate to oxaloacetate. This results in the anaplerotic reprogramming of lung vascular cells and their subsequent proliferation. Treatment of sugen/hypoxia rats with the PC inhibitor, phenylacetic acid 20 mg/kg, starting after one week from disease induction, significantly attenuated right ventricular systolic pressure, Fulton index, and pulmonary vascular cell proliferation. PC inhibition reduced the glycolytic shift by attenuating Akt-signaling, glycolysis, and restored mitochondrial pyruvate oxidation. Our findings suggest that targeting PC mediated anaplerosis is a potential therapeutic intervention for the resolution of vascular remodeling in PAH.

Original languageEnglish (US)
Article number443
JournalJournal of Clinical Medicine
Volume9
Issue number2
DOIs
StatePublished - Feb 2020

Keywords

  • Anaplerosis
  • Glucose oxidation
  • Glycolysis
  • Oxaloacetate
  • Pulmonary arterial hypertension
  • Pyruvate carboxylase inhibitor
  • Pyruvate dehydrogenase

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint

Dive into the research topics of 'Inhibition of anaplerosis attenuated vascular proliferation in pulmonary arterial hypertension'. Together they form a unique fingerprint.

Cite this