Abnormal mitochondrial L-arginine transport contributes to the pathogenesis of heart failure and rexoygenation injury.

<h4>Background</h4>Impaired mitochondrial function is fundamental feature of heart failure (HF) and myocardial ischemia. In addition to the effects of heightened oxidative stress, altered nitric oxide (NO) metabolism, generated by a mitochondrial NO synthase, has also been proposed to im...

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Autores principales:	David Williams, Kylie M Venardos, Melissa Byrne, Mandar Joshi, Duncan Horlock, Nicholas T Lam, Paul Gregorevic, Sean L McGee, David M Kaye
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f11909e9fbd049feb59ddde30b0a8a64
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spelling	oai:doaj.org-article:f11909e9fbd049feb59ddde30b0a8a642021-11-25T06:05:18ZAbnormal mitochondrial L-arginine transport contributes to the pathogenesis of heart failure and rexoygenation injury.1932-620310.1371/journal.pone.0104643https://doaj.org/article/f11909e9fbd049feb59ddde30b0a8a642014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25111602/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Impaired mitochondrial function is fundamental feature of heart failure (HF) and myocardial ischemia. In addition to the effects of heightened oxidative stress, altered nitric oxide (NO) metabolism, generated by a mitochondrial NO synthase, has also been proposed to impact upon mitochondrial function. However, the mechanism responsible for arginine transport into mitochondria and the effect of HF on such a process is unknown. We therefore aimed to characterize mitochondrial L-arginine transport and to investigate the hypothesis that impaired mitochondrial L-arginine transport plays a key role in the pathogenesis of heart failure and myocardial injury.<h4>Methods and results</h4>In mitochondria isolated from failing hearts (sheep rapid pacing model and mouse Mst1 transgenic model) we demonstrated a marked reduction in L-arginine uptake (p<0.05 and p<0.01 respectively) and expression of the principal L-arginine transporter, CAT-1 (p<0.001, p<0.01) compared to controls. This was accompanied by significantly lower NO production and higher 3-nitrotyrosine levels (both p<0.05). The role of mitochondrial L-arginine transport in modulating cardiac stress responses was examined in cardiomyocytes with mitochondrial specific overexpression of CAT-1 (mtCAT1) exposed to hypoxia-reoxygenation stress. mtCAT1 cardiomyocytes had significantly improved mitochondrial membrane potential, respiration and ATP turnover together with significantly decreased reactive oxygen species production and cell death following mitochondrial stress.<h4>Conclusion</h4>These data provide new insights into the role of L-arginine transport in mitochondrial biology and cardiovascular disease. Augmentation of mitochondrial L-arginine availability may be a novel therapeutic strategy for myocardial disorders involving mitochondrial stress such as heart failure and reperfusion injury.David WilliamsKylie M VenardosMelissa ByrneMandar JoshiDuncan HorlockNicholas T LamPaul GregorevicSean L McGeeDavid M KayePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 8, p e104643 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q David Williams Kylie M Venardos Melissa Byrne Mandar Joshi Duncan Horlock Nicholas T Lam Paul Gregorevic Sean L McGee David M Kaye Abnormal mitochondrial L-arginine transport contributes to the pathogenesis of heart failure and rexoygenation injury.
description	<h4>Background</h4>Impaired mitochondrial function is fundamental feature of heart failure (HF) and myocardial ischemia. In addition to the effects of heightened oxidative stress, altered nitric oxide (NO) metabolism, generated by a mitochondrial NO synthase, has also been proposed to impact upon mitochondrial function. However, the mechanism responsible for arginine transport into mitochondria and the effect of HF on such a process is unknown. We therefore aimed to characterize mitochondrial L-arginine transport and to investigate the hypothesis that impaired mitochondrial L-arginine transport plays a key role in the pathogenesis of heart failure and myocardial injury.<h4>Methods and results</h4>In mitochondria isolated from failing hearts (sheep rapid pacing model and mouse Mst1 transgenic model) we demonstrated a marked reduction in L-arginine uptake (p<0.05 and p<0.01 respectively) and expression of the principal L-arginine transporter, CAT-1 (p<0.001, p<0.01) compared to controls. This was accompanied by significantly lower NO production and higher 3-nitrotyrosine levels (both p<0.05). The role of mitochondrial L-arginine transport in modulating cardiac stress responses was examined in cardiomyocytes with mitochondrial specific overexpression of CAT-1 (mtCAT1) exposed to hypoxia-reoxygenation stress. mtCAT1 cardiomyocytes had significantly improved mitochondrial membrane potential, respiration and ATP turnover together with significantly decreased reactive oxygen species production and cell death following mitochondrial stress.<h4>Conclusion</h4>These data provide new insights into the role of L-arginine transport in mitochondrial biology and cardiovascular disease. Augmentation of mitochondrial L-arginine availability may be a novel therapeutic strategy for myocardial disorders involving mitochondrial stress such as heart failure and reperfusion injury.
format	article
author	David Williams Kylie M Venardos Melissa Byrne Mandar Joshi Duncan Horlock Nicholas T Lam Paul Gregorevic Sean L McGee David M Kaye
author_facet	David Williams Kylie M Venardos Melissa Byrne Mandar Joshi Duncan Horlock Nicholas T Lam Paul Gregorevic Sean L McGee David M Kaye
author_sort	David Williams
title	Abnormal mitochondrial L-arginine transport contributes to the pathogenesis of heart failure and rexoygenation injury.
title_short	Abnormal mitochondrial L-arginine transport contributes to the pathogenesis of heart failure and rexoygenation injury.
title_full	Abnormal mitochondrial L-arginine transport contributes to the pathogenesis of heart failure and rexoygenation injury.
title_fullStr	Abnormal mitochondrial L-arginine transport contributes to the pathogenesis of heart failure and rexoygenation injury.
title_full_unstemmed	Abnormal mitochondrial L-arginine transport contributes to the pathogenesis of heart failure and rexoygenation injury.
title_sort	abnormal mitochondrial l-arginine transport contributes to the pathogenesis of heart failure and rexoygenation injury.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/f11909e9fbd049feb59ddde30b0a8a64
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Abnormal mitochondrial L-arginine transport contributes to the pathogenesis of heart failure and rexoygenation injury.

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