論文 - 詳細
| RRC ID | 12545 |
|---|---|
| 著者 | McDermott-Roe C, Ye J, Ahmed R, Sun XM, Serafín A, Ware J, Bottolo L, Muckett P, Cañas X, Zhang J, Rowe GC, Buchan R, Lu H, Braithwaite A, Mancini M, Hauton D, Martí R, García-Arumí E, Hubner N, Jacob H, Serikawa T, Zidek V, Papousek F, Kolar F, Cardona M, Ruiz-Meana M, García-Dorado D, Comella JX, Felkin LE, Barton PJ, Arany Z, Pravenec M, Petretto E, Sanchis D, Cook SA. |
| タイトル | Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function. |
| ジャーナル | Nature |
| Abstract |
Left ventricular mass (LVM) is a highly heritable trait and an independent risk factor for all-cause mortality. So far, genome-wide association studies have not identified the genetic factors that underlie LVM variation, and the regulatory mechanisms for blood-pressure-independent cardiac hypertrophy remain poorly understood. Unbiased systems genetics approaches in the rat now provide a powerful complementary tool to genome-wide association studies, and we applied integrative genomics to dissect a highly replicated, blood-pressure-independent LVM locus on rat chromosome 3p. Here we identified endonuclease G (Endog), which previously was implicated in apoptosis but not hypertrophy, as the gene at the locus, and we found a loss-of-function mutation in Endog that is associated with increased LVM and impaired cardiac function. Inhibition of Endog in cultured cardiomyocytes resulted in an increase in cell size and hypertrophic biomarkers in the absence of pro-hypertrophic stimulation. Genome-wide network analysis unexpectedly implicated ENDOG in fundamental mitochondrial processes that are unrelated to apoptosis. We showed direct regulation of ENDOG by ERR-α and PGC1α (which are master regulators of mitochondrial and cardiac function), interaction of ENDOG with the mitochondrial genome and ENDOG-mediated regulation of mitochondrial mass. At baseline, the Endog-deleted mouse heart had depleted mitochondria, mitochondrial dysfunction and elevated levels of reactive oxygen species, which were associated with enlarged and steatotic cardiomyocytes. Our study has further established the link between mitochondrial dysfunction, reactive oxygen species and heart disease and has uncovered a role for Endog in maladaptive cardiac hypertrophy. |
| 巻・号 | 478(7367) |
| ページ | 114-8 |
| 公開日 | 2011-10-5 |
| DOI | 10.1038/nature10490 |
| PII | nature10490 |
| PMID | 21979051 |
| PMC | PMC3189541 |
| MeSH | Animals Apoptosis Body Weight / genetics Cardiomegaly / enzymology* Cardiomegaly / genetics Cardiomegaly / pathology* Cardiomegaly / physiopathology Cell Respiration Chromosomes, Mammalian / genetics Crosses, Genetic Endodeoxyribonucleases / deficiency Endodeoxyribonucleases / genetics Endodeoxyribonucleases / metabolism* Female Gene Expression Regulation Genes, Mitochondrial / genetics Hypertrophy, Left Ventricular / enzymology Hypertrophy, Left Ventricular / genetics Hypertrophy, Left Ventricular / pathology Hypertrophy, Left Ventricular / physiopathology Lipid Metabolism Male Mitochondria / genetics Mitochondria / metabolism* Mitochondria / pathology Organ Size / genetics Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Quantitative Trait Loci / genetics RNA-Binding Proteins / metabolism Rats Rats, Inbred Strains Reactive Oxygen Species / metabolism Receptors, Estrogen / metabolism Transcription Factors / metabolism |
| IF | 42.779 |
| 引用数 | 90 |
| WOS 分野 | BIOCHEMISTRY & MOLECULAR BIOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 8 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ラット | SHR/Kyo(strainID=9) |