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Ndufc2 Gene Inhibition Is Associated With Mitochondrial Dysfunction and Increased Stroke Susceptibility in an Animal Model of Complex Human Disease

BACKGROUND: The genetic basis of stroke susceptibility remains to be elucidated. STR1 quantitative trait locus (STR1/QTL) was identified on rat chromosome 1 of stroke‐prone spontaneously hypertensive rat (SHRSP) upon Japanese‐style stroke‐permissive diet (JD), and it contributes to 20% of the stroke...

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Autores principales: Rubattu, Speranza, Di Castro, Sara, Schulz, Herbert, Geurts, Aron M., Cotugno, Maria, Bianchi, Franca, Maatz, Henrike, Hummel, Oliver, Falak, Samreen, Stanzione, Rosita, Marchitti, Simona, Scarpino, Stefania, Giusti, Betti, Kura, Ada, Gensini, Gian Franco, Peyvandi, Flora, Mannucci, Pier Mannuccio, Rasura, Maurizia, Sciarretta, Sebastiano, Dwinell, Melinda R., Hubner, Norbert, Volpe, Massimo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4802485/
https://www.ncbi.nlm.nih.gov/pubmed/26888427
http://dx.doi.org/10.1161/JAHA.115.002701
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author Rubattu, Speranza
Di Castro, Sara
Schulz, Herbert
Geurts, Aron M.
Cotugno, Maria
Bianchi, Franca
Maatz, Henrike
Hummel, Oliver
Falak, Samreen
Stanzione, Rosita
Marchitti, Simona
Scarpino, Stefania
Giusti, Betti
Kura, Ada
Gensini, Gian Franco
Peyvandi, Flora
Mannucci, Pier Mannuccio
Rasura, Maurizia
Sciarretta, Sebastiano
Dwinell, Melinda R.
Hubner, Norbert
Volpe, Massimo
author_facet Rubattu, Speranza
Di Castro, Sara
Schulz, Herbert
Geurts, Aron M.
Cotugno, Maria
Bianchi, Franca
Maatz, Henrike
Hummel, Oliver
Falak, Samreen
Stanzione, Rosita
Marchitti, Simona
Scarpino, Stefania
Giusti, Betti
Kura, Ada
Gensini, Gian Franco
Peyvandi, Flora
Mannucci, Pier Mannuccio
Rasura, Maurizia
Sciarretta, Sebastiano
Dwinell, Melinda R.
Hubner, Norbert
Volpe, Massimo
author_sort Rubattu, Speranza
collection PubMed
description BACKGROUND: The genetic basis of stroke susceptibility remains to be elucidated. STR1 quantitative trait locus (STR1/QTL) was identified on rat chromosome 1 of stroke‐prone spontaneously hypertensive rat (SHRSP) upon Japanese‐style stroke‐permissive diet (JD), and it contributes to 20% of the stroke phenotype variance. METHODS AND RESULTS: Nine hundred eighty‐six probe sets mapping on STR1 were selected from the Rat RAE230A array and screened through a microarray differential expression analysis in brains of SHRSP and stroke‐resistant SHR (SHRSR) fed with either regular diet or JD. The gene encoding Ndufc2 (NADH dehydrogenase [ubiquinone] 1 subunit), mapping 8 Mb apart from STR1/QTL Lod score peak, was found significantly down‐regulated under JD in SHRSP compared to SHRSR. Ndufc2 disruption altered complex I assembly and activity, reduced mitochondrial membrane potential and ATP levels, and increased reactive oxygen species production and inflammation both in vitro and in vivo. SHRSR carrying heterozygous Ndufc2 deletion showed renal abnormalities and stroke occurrence under JD, similarly to SHRSP. In humans, T allele variant at NDUFC2/rs11237379 was associated with significant reduction in gene expression and with increased occurrence of early‐onset ischemic stroke by recessive mode of transmission (odds ratio [OR], 1.39; CI, 1.07–1.80; P=0.012). Subjects carrying TT/rs11237379 and A allele variant at NDUFC2/rs641836 had further increased risk of stroke (OR=1.56; CI, 1.14–2.13; P=0.006). CONCLUSIONS: A significant reduction of Ndufc2 expression causes complex I dysfunction and contributes to stroke susceptibility in SHRSP. Moreover, our current evidence may suggest that Ndufc2 can contribute to an increased occurrence of early‐onset ischemic stroke in humans.
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spelling pubmed-48024852016-04-08 Ndufc2 Gene Inhibition Is Associated With Mitochondrial Dysfunction and Increased Stroke Susceptibility in an Animal Model of Complex Human Disease Rubattu, Speranza Di Castro, Sara Schulz, Herbert Geurts, Aron M. Cotugno, Maria Bianchi, Franca Maatz, Henrike Hummel, Oliver Falak, Samreen Stanzione, Rosita Marchitti, Simona Scarpino, Stefania Giusti, Betti Kura, Ada Gensini, Gian Franco Peyvandi, Flora Mannucci, Pier Mannuccio Rasura, Maurizia Sciarretta, Sebastiano Dwinell, Melinda R. Hubner, Norbert Volpe, Massimo J Am Heart Assoc Original Research BACKGROUND: The genetic basis of stroke susceptibility remains to be elucidated. STR1 quantitative trait locus (STR1/QTL) was identified on rat chromosome 1 of stroke‐prone spontaneously hypertensive rat (SHRSP) upon Japanese‐style stroke‐permissive diet (JD), and it contributes to 20% of the stroke phenotype variance. METHODS AND RESULTS: Nine hundred eighty‐six probe sets mapping on STR1 were selected from the Rat RAE230A array and screened through a microarray differential expression analysis in brains of SHRSP and stroke‐resistant SHR (SHRSR) fed with either regular diet or JD. The gene encoding Ndufc2 (NADH dehydrogenase [ubiquinone] 1 subunit), mapping 8 Mb apart from STR1/QTL Lod score peak, was found significantly down‐regulated under JD in SHRSP compared to SHRSR. Ndufc2 disruption altered complex I assembly and activity, reduced mitochondrial membrane potential and ATP levels, and increased reactive oxygen species production and inflammation both in vitro and in vivo. SHRSR carrying heterozygous Ndufc2 deletion showed renal abnormalities and stroke occurrence under JD, similarly to SHRSP. In humans, T allele variant at NDUFC2/rs11237379 was associated with significant reduction in gene expression and with increased occurrence of early‐onset ischemic stroke by recessive mode of transmission (odds ratio [OR], 1.39; CI, 1.07–1.80; P=0.012). Subjects carrying TT/rs11237379 and A allele variant at NDUFC2/rs641836 had further increased risk of stroke (OR=1.56; CI, 1.14–2.13; P=0.006). CONCLUSIONS: A significant reduction of Ndufc2 expression causes complex I dysfunction and contributes to stroke susceptibility in SHRSP. Moreover, our current evidence may suggest that Ndufc2 can contribute to an increased occurrence of early‐onset ischemic stroke in humans. John Wiley and Sons Inc. 2016-02-17 /pmc/articles/PMC4802485/ /pubmed/26888427 http://dx.doi.org/10.1161/JAHA.115.002701 Text en © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial (http://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 Original Research
Rubattu, Speranza
Di Castro, Sara
Schulz, Herbert
Geurts, Aron M.
Cotugno, Maria
Bianchi, Franca
Maatz, Henrike
Hummel, Oliver
Falak, Samreen
Stanzione, Rosita
Marchitti, Simona
Scarpino, Stefania
Giusti, Betti
Kura, Ada
Gensini, Gian Franco
Peyvandi, Flora
Mannucci, Pier Mannuccio
Rasura, Maurizia
Sciarretta, Sebastiano
Dwinell, Melinda R.
Hubner, Norbert
Volpe, Massimo
Ndufc2 Gene Inhibition Is Associated With Mitochondrial Dysfunction and Increased Stroke Susceptibility in an Animal Model of Complex Human Disease
title Ndufc2 Gene Inhibition Is Associated With Mitochondrial Dysfunction and Increased Stroke Susceptibility in an Animal Model of Complex Human Disease
title_full Ndufc2 Gene Inhibition Is Associated With Mitochondrial Dysfunction and Increased Stroke Susceptibility in an Animal Model of Complex Human Disease
title_fullStr Ndufc2 Gene Inhibition Is Associated With Mitochondrial Dysfunction and Increased Stroke Susceptibility in an Animal Model of Complex Human Disease
title_full_unstemmed Ndufc2 Gene Inhibition Is Associated With Mitochondrial Dysfunction and Increased Stroke Susceptibility in an Animal Model of Complex Human Disease
title_short Ndufc2 Gene Inhibition Is Associated With Mitochondrial Dysfunction and Increased Stroke Susceptibility in an Animal Model of Complex Human Disease
title_sort ndufc2 gene inhibition is associated with mitochondrial dysfunction and increased stroke susceptibility in an animal model of complex human disease
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4802485/
https://www.ncbi.nlm.nih.gov/pubmed/26888427
http://dx.doi.org/10.1161/JAHA.115.002701
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