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Inhibition of Anaplerosis Attenuated Vascular Proliferation in Pulmonary Arterial Hypertension

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...

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Autores principales: Valuparampil Varghese, Mathews, James, Joel, Eccles, Cody A, Niihori, Maki, Rafikova, Olga, Rafikov, Ruslan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074087/
https://www.ncbi.nlm.nih.gov/pubmed/32041182
http://dx.doi.org/10.3390/jcm9020443
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author Valuparampil Varghese, Mathews
James, Joel
Eccles, Cody A
Niihori, Maki
Rafikova, Olga
Rafikov, Ruslan
author_facet Valuparampil Varghese, Mathews
James, Joel
Eccles, Cody A
Niihori, Maki
Rafikova, Olga
Rafikov, Ruslan
author_sort Valuparampil Varghese, Mathews
collection PubMed
description 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.
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spelling pubmed-70740872020-03-19 Inhibition of Anaplerosis Attenuated Vascular Proliferation in Pulmonary Arterial Hypertension Valuparampil Varghese, Mathews James, Joel Eccles, Cody A Niihori, Maki Rafikova, Olga Rafikov, Ruslan J Clin Med Article 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. MDPI 2020-02-06 /pmc/articles/PMC7074087/ /pubmed/32041182 http://dx.doi.org/10.3390/jcm9020443 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Valuparampil Varghese, Mathews
James, Joel
Eccles, Cody A
Niihori, Maki
Rafikova, Olga
Rafikov, Ruslan
Inhibition of Anaplerosis Attenuated Vascular Proliferation in Pulmonary Arterial Hypertension
title Inhibition of Anaplerosis Attenuated Vascular Proliferation in Pulmonary Arterial Hypertension
title_full Inhibition of Anaplerosis Attenuated Vascular Proliferation in Pulmonary Arterial Hypertension
title_fullStr Inhibition of Anaplerosis Attenuated Vascular Proliferation in Pulmonary Arterial Hypertension
title_full_unstemmed Inhibition of Anaplerosis Attenuated Vascular Proliferation in Pulmonary Arterial Hypertension
title_short Inhibition of Anaplerosis Attenuated Vascular Proliferation in Pulmonary Arterial Hypertension
title_sort inhibition of anaplerosis attenuated vascular proliferation in pulmonary arterial hypertension
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074087/
https://www.ncbi.nlm.nih.gov/pubmed/32041182
http://dx.doi.org/10.3390/jcm9020443
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