Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1782422731632934912 |
---|---|
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. |
format | Online Article Text |
id | pubmed-4802485 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT rubattusperanza ndufc2geneinhibitionisassociatedwithmitochondrialdysfunctionandincreasedstrokesusceptibilityinananimalmodelofcomplexhumandisease AT dicastrosara ndufc2geneinhibitionisassociatedwithmitochondrialdysfunctionandincreasedstrokesusceptibilityinananimalmodelofcomplexhumandisease AT schulzherbert ndufc2geneinhibitionisassociatedwithmitochondrialdysfunctionandincreasedstrokesusceptibilityinananimalmodelofcomplexhumandisease AT geurtsaronm ndufc2geneinhibitionisassociatedwithmitochondrialdysfunctionandincreasedstrokesusceptibilityinananimalmodelofcomplexhumandisease AT cotugnomaria ndufc2geneinhibitionisassociatedwithmitochondrialdysfunctionandincreasedstrokesusceptibilityinananimalmodelofcomplexhumandisease AT bianchifranca ndufc2geneinhibitionisassociatedwithmitochondrialdysfunctionandincreasedstrokesusceptibilityinananimalmodelofcomplexhumandisease AT maatzhenrike ndufc2geneinhibitionisassociatedwithmitochondrialdysfunctionandincreasedstrokesusceptibilityinananimalmodelofcomplexhumandisease AT hummeloliver ndufc2geneinhibitionisassociatedwithmitochondrialdysfunctionandincreasedstrokesusceptibilityinananimalmodelofcomplexhumandisease AT falaksamreen ndufc2geneinhibitionisassociatedwithmitochondrialdysfunctionandincreasedstrokesusceptibilityinananimalmodelofcomplexhumandisease AT stanzionerosita ndufc2geneinhibitionisassociatedwithmitochondrialdysfunctionandincreasedstrokesusceptibilityinananimalmodelofcomplexhumandisease AT marchittisimona ndufc2geneinhibitionisassociatedwithmitochondrialdysfunctionandincreasedstrokesusceptibilityinananimalmodelofcomplexhumandisease AT scarpinostefania ndufc2geneinhibitionisassociatedwithmitochondrialdysfunctionandincreasedstrokesusceptibilityinananimalmodelofcomplexhumandisease AT giustibetti ndufc2geneinhibitionisassociatedwithmitochondrialdysfunctionandincreasedstrokesusceptibilityinananimalmodelofcomplexhumandisease AT kuraada ndufc2geneinhibitionisassociatedwithmitochondrialdysfunctionandincreasedstrokesusceptibilityinananimalmodelofcomplexhumandisease AT gensinigianfranco ndufc2geneinhibitionisassociatedwithmitochondrialdysfunctionandincreasedstrokesusceptibilityinananimalmodelofcomplexhumandisease AT peyvandiflora ndufc2geneinhibitionisassociatedwithmitochondrialdysfunctionandincreasedstrokesusceptibilityinananimalmodelofcomplexhumandisease AT mannuccipiermannuccio ndufc2geneinhibitionisassociatedwithmitochondrialdysfunctionandincreasedstrokesusceptibilityinananimalmodelofcomplexhumandisease AT rasuramaurizia ndufc2geneinhibitionisassociatedwithmitochondrialdysfunctionandincreasedstrokesusceptibilityinananimalmodelofcomplexhumandisease AT sciarrettasebastiano ndufc2geneinhibitionisassociatedwithmitochondrialdysfunctionandincreasedstrokesusceptibilityinananimalmodelofcomplexhumandisease AT dwinellmelindar ndufc2geneinhibitionisassociatedwithmitochondrialdysfunctionandincreasedstrokesusceptibilityinananimalmodelofcomplexhumandisease AT hubnernorbert ndufc2geneinhibitionisassociatedwithmitochondrialdysfunctionandincreasedstrokesusceptibilityinananimalmodelofcomplexhumandisease AT volpemassimo ndufc2geneinhibitionisassociatedwithmitochondrialdysfunctionandincreasedstrokesusceptibilityinananimalmodelofcomplexhumandisease |