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J Am Heart Assoc. 2016 Feb 17;5(2). pii: e002701. doi: 10.1161/JAHA.115.002701.

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

Author information

1
IRCCS Neuromed, Pozzilli (Isernia), Italy Department of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University of Rome, Ospedale S. Andrea, Rome, Italy rubattu.speranza@neuromed.it.
2
IRCCS Neuromed, Pozzilli (Isernia), Italy.
3
Zentrum fur Molecular Medicine-MDC, Berlin, Germany.
4
Department of Physiology and Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI.
5
Department of Cytology and Histology, School of Medicine and Psychology, University Sapienza of Rome, Ospedale S. Andrea, Rome, Itlay.
6
Department of Experimental and Clinical Medicine, University of Florence, Italy Atherothrombotic Disease Center, AOU Careggi, Florence, Italy.
7
Department of Experimental and Clinical Medicine, University of Florence, Italy Department of Cardiothoracovascular Medicine, AOU Careggi, Florence, Italy Don Carlo Gnocchi Foundation, Florence, Italy.
8
IRCCS Ca' Granda Maggiore Policlinico Hospital Foundation, Milan, Italy.
9
Stroke Unit, School of Medicine and Psychology, Sapienza University of Rome, Ospedale S. Andrea, Rome, Italy.
10
IRCCS Neuromed, Pozzilli (Isernia), Italy Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.
11
IRCCS Neuromed, Pozzilli (Isernia), Italy Department of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University of Rome, Ospedale S. Andrea, Rome, Italy.

Abstract

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.

KEYWORDS:

Ndufc2; complex I; early‐onset ischemic stroke; knockout rat model; mitochondria; stroke‐prone spontaneously hypertensive rat

PMID:
26888427
PMCID:
PMC4802485
DOI:
10.1161/JAHA.115.002701
[Indexed for MEDLINE]
Free PMC Article

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