Cargando…

l‐Carnitine therapy improves right heart dysfunction through Cpt1‐dependent fatty acid oxidation

Pulmonary arterial hypertension (PAH) is a fatal vasculopathy that ultimately leads to elevated pulmonary pressure and death by right ventricular (RV) failure, which occurs in part due to decreased fatty acid oxidation and cytotoxic lipid accumulation. In this study, we tested the hypothesis that de...

Descripción completa

Detalles Bibliográficos
Autores principales: Agrawal, Vineet, Hemnes, Anna R., Shelburne, Nicholas J., Fortune, Niki, Fuentes, Julio L., Colvin, Dan, Calcutt, Marion W., Talati, Megha, Poovey, Emily, West, James D., Brittain, Evan L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9326551/
https://www.ncbi.nlm.nih.gov/pubmed/35911183
http://dx.doi.org/10.1002/pul2.12107
_version_ 1784757312339050496
author Agrawal, Vineet
Hemnes, Anna R.
Shelburne, Nicholas J.
Fortune, Niki
Fuentes, Julio L.
Colvin, Dan
Calcutt, Marion W.
Talati, Megha
Poovey, Emily
West, James D.
Brittain, Evan L.
author_facet Agrawal, Vineet
Hemnes, Anna R.
Shelburne, Nicholas J.
Fortune, Niki
Fuentes, Julio L.
Colvin, Dan
Calcutt, Marion W.
Talati, Megha
Poovey, Emily
West, James D.
Brittain, Evan L.
author_sort Agrawal, Vineet
collection PubMed
description Pulmonary arterial hypertension (PAH) is a fatal vasculopathy that ultimately leads to elevated pulmonary pressure and death by right ventricular (RV) failure, which occurs in part due to decreased fatty acid oxidation and cytotoxic lipid accumulation. In this study, we tested the hypothesis that decreased fatty acid oxidation and increased lipid accumulation in the failing RV is driven, in part, by a relative carnitine deficiency. We then tested whether supplementation of l‐carnitine can reverse lipotoxic RV failure through augmentation of fatty acid oxidation. In vivo in transgenic mice harboring a human BMPR2 mutation, l‐carnitine supplementation reversed RV failure by increasing RV cardiac output, improving RV ejection fraction, and decreasing RV lipid accumulation through increased PPARγ expression and augmented fatty acid oxidation of long chain fatty acids. These findings were confirmed in a second model of pulmonary artery banding‐induced RV dysfunction. In vitro, l‐carnitine supplementation selectively increased fatty acid oxidation in mitochondria and decreased lipid accumulation through a Cpt1‐dependent pathway. l‐Carnitine supplementation improves right ventricular contractility in the stressed RV through augmentation of fatty acid oxidation and decreases lipid accumulation. Correction of carnitine deficiency through l‐carnitine supplementation in PAH may reverse RV failure.
format Online
Article
Text
id pubmed-9326551
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-93265512022-07-30 l‐Carnitine therapy improves right heart dysfunction through Cpt1‐dependent fatty acid oxidation Agrawal, Vineet Hemnes, Anna R. Shelburne, Nicholas J. Fortune, Niki Fuentes, Julio L. Colvin, Dan Calcutt, Marion W. Talati, Megha Poovey, Emily West, James D. Brittain, Evan L. Pulm Circ Research Articles Pulmonary arterial hypertension (PAH) is a fatal vasculopathy that ultimately leads to elevated pulmonary pressure and death by right ventricular (RV) failure, which occurs in part due to decreased fatty acid oxidation and cytotoxic lipid accumulation. In this study, we tested the hypothesis that decreased fatty acid oxidation and increased lipid accumulation in the failing RV is driven, in part, by a relative carnitine deficiency. We then tested whether supplementation of l‐carnitine can reverse lipotoxic RV failure through augmentation of fatty acid oxidation. In vivo in transgenic mice harboring a human BMPR2 mutation, l‐carnitine supplementation reversed RV failure by increasing RV cardiac output, improving RV ejection fraction, and decreasing RV lipid accumulation through increased PPARγ expression and augmented fatty acid oxidation of long chain fatty acids. These findings were confirmed in a second model of pulmonary artery banding‐induced RV dysfunction. In vitro, l‐carnitine supplementation selectively increased fatty acid oxidation in mitochondria and decreased lipid accumulation through a Cpt1‐dependent pathway. l‐Carnitine supplementation improves right ventricular contractility in the stressed RV through augmentation of fatty acid oxidation and decreases lipid accumulation. Correction of carnitine deficiency through l‐carnitine supplementation in PAH may reverse RV failure. John Wiley and Sons Inc. 2022-07-01 /pmc/articles/PMC9326551/ /pubmed/35911183 http://dx.doi.org/10.1002/pul2.12107 Text en © 2022 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Research Articles
Agrawal, Vineet
Hemnes, Anna R.
Shelburne, Nicholas J.
Fortune, Niki
Fuentes, Julio L.
Colvin, Dan
Calcutt, Marion W.
Talati, Megha
Poovey, Emily
West, James D.
Brittain, Evan L.
l‐Carnitine therapy improves right heart dysfunction through Cpt1‐dependent fatty acid oxidation
title l‐Carnitine therapy improves right heart dysfunction through Cpt1‐dependent fatty acid oxidation
title_full l‐Carnitine therapy improves right heart dysfunction through Cpt1‐dependent fatty acid oxidation
title_fullStr l‐Carnitine therapy improves right heart dysfunction through Cpt1‐dependent fatty acid oxidation
title_full_unstemmed l‐Carnitine therapy improves right heart dysfunction through Cpt1‐dependent fatty acid oxidation
title_short l‐Carnitine therapy improves right heart dysfunction through Cpt1‐dependent fatty acid oxidation
title_sort l‐carnitine therapy improves right heart dysfunction through cpt1‐dependent fatty acid oxidation
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9326551/
https://www.ncbi.nlm.nih.gov/pubmed/35911183
http://dx.doi.org/10.1002/pul2.12107
work_keys_str_mv AT agrawalvineet lcarnitinetherapyimprovesrightheartdysfunctionthroughcpt1dependentfattyacidoxidation
AT hemnesannar lcarnitinetherapyimprovesrightheartdysfunctionthroughcpt1dependentfattyacidoxidation
AT shelburnenicholasj lcarnitinetherapyimprovesrightheartdysfunctionthroughcpt1dependentfattyacidoxidation
AT fortuneniki lcarnitinetherapyimprovesrightheartdysfunctionthroughcpt1dependentfattyacidoxidation
AT fuentesjuliol lcarnitinetherapyimprovesrightheartdysfunctionthroughcpt1dependentfattyacidoxidation
AT colvindan lcarnitinetherapyimprovesrightheartdysfunctionthroughcpt1dependentfattyacidoxidation
AT calcuttmarionw lcarnitinetherapyimprovesrightheartdysfunctionthroughcpt1dependentfattyacidoxidation
AT talatimegha lcarnitinetherapyimprovesrightheartdysfunctionthroughcpt1dependentfattyacidoxidation
AT pooveyemily lcarnitinetherapyimprovesrightheartdysfunctionthroughcpt1dependentfattyacidoxidation
AT westjamesd lcarnitinetherapyimprovesrightheartdysfunctionthroughcpt1dependentfattyacidoxidation
AT brittainevanl lcarnitinetherapyimprovesrightheartdysfunctionthroughcpt1dependentfattyacidoxidation