Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function
Left ventricular mass (LVM) is a highly heritable trait1 and an independent risk factor for all-cause mortality2. To date, genome-wide association studies (GWASs) have not identified the genetic factors underlying LVM variation3 and the regulatory mechanisms for blood pressure (BP)-independent cardi...
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2011
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3189541/ |
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pubmed-31895412012-04-05 Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function McDermott-Roe, Chris Ye, Junmei Ahmed, Rizwan Sun, Xi-Ming Serafín, Anna Ware, James Bottolo, Leonardo Muckett, Phil Cañas, Xavier Zhang, Jisheng Rowe, Glenn C. Buchan, Rachel Lu, Han Braithwaite, Adam Mancini, Massimiliano Hauton, David Martí, Ramon García-Arumí, Elena Hubner, Norbert Jacob, Howard Serikawa, Tadao Zidek, Vaclav Papousek, Frantisek Kolar, Frantisek Cardona, Maria Ruiz-Meana, Marisol García-Dorado, David Comella, Joan X Felkin, Leanne E Barton, Paul JR Arany, Zoltan Pravenec, Michal Petretto, Enrico Sanchis, Daniel Cook, Stuart A. Article Left ventricular mass (LVM) is a highly heritable trait1 and an independent risk factor for all-cause mortality2. To date, genome-wide association studies (GWASs) have not identified the genetic factors underlying LVM variation3 and the regulatory mechanisms for blood pressure (BP)-independent cardiac hypertrophy remain poorly understood4,5. Unbiased systems-genetics approaches in the rat6,7 now provide a powerful complementary tool to GWAS and we applied integrative genomics to dissect a highly replicated, BP-independent LVM locus on rat chromosome 3p. We identified endonuclease G (Endog), previously implicated in apoptosis8 but not hypertrophy, as the gene at the locus and demonstrated loss-of-function mutation in Endog 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 inferred ENDOG in fundamental mitochondrial processes unrelated to apoptosis. We showed direct regulation of ENDOG by ERRα and PGC1α, master regulators of mitochondrial and cardiac function9,10,11, interaction of ENDOG with the mitochondrial genome and ENDOG-mediated regulation of mitochondrial mass. At baseline, Endog deleted mouse heart had depleted mitochondria, mitochondrial dysfunction and elevated reactive oxygen species (ROS), which was associated with enlarged and steatotic cardiomyocytes. Our studies establish further the link between mitochondrial dysfunction, ROS and heart disease and demonstrate a new role for Endog in maladaptive cardiac hypertrophy. 2011-10-05 /pmc/articles/PMC3189541/ /pubmed/21979051 http://dx.doi.org/10.1038/nature10490 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
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Open Access Journal |
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Foreign Institution |
| institution |
US National Center for Biotechnology Information |
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NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
McDermott-Roe, Chris Ye, Junmei Ahmed, Rizwan Sun, Xi-Ming Serafín, Anna Ware, James Bottolo, Leonardo Muckett, Phil Cañas, Xavier Zhang, Jisheng Rowe, Glenn C. Buchan, Rachel Lu, Han Braithwaite, Adam Mancini, Massimiliano Hauton, David Martí, Ramon García-Arumí, Elena Hubner, Norbert Jacob, Howard Serikawa, Tadao Zidek, Vaclav Papousek, Frantisek Kolar, Frantisek Cardona, Maria Ruiz-Meana, Marisol García-Dorado, David Comella, Joan X Felkin, Leanne E Barton, Paul JR Arany, Zoltan Pravenec, Michal Petretto, Enrico Sanchis, Daniel Cook, Stuart A. |
| spellingShingle |
McDermott-Roe, Chris Ye, Junmei Ahmed, Rizwan Sun, Xi-Ming Serafín, Anna Ware, James Bottolo, Leonardo Muckett, Phil Cañas, Xavier Zhang, Jisheng Rowe, Glenn C. Buchan, Rachel Lu, Han Braithwaite, Adam Mancini, Massimiliano Hauton, David Martí, Ramon García-Arumí, Elena Hubner, Norbert Jacob, Howard Serikawa, Tadao Zidek, Vaclav Papousek, Frantisek Kolar, Frantisek Cardona, Maria Ruiz-Meana, Marisol García-Dorado, David Comella, Joan X Felkin, Leanne E Barton, Paul JR Arany, Zoltan Pravenec, Michal Petretto, Enrico Sanchis, Daniel Cook, Stuart A. Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function |
| author_facet |
McDermott-Roe, Chris Ye, Junmei Ahmed, Rizwan Sun, Xi-Ming Serafín, Anna Ware, James Bottolo, Leonardo Muckett, Phil Cañas, Xavier Zhang, Jisheng Rowe, Glenn C. Buchan, Rachel Lu, Han Braithwaite, Adam Mancini, Massimiliano Hauton, David Martí, Ramon García-Arumí, Elena Hubner, Norbert Jacob, Howard Serikawa, Tadao Zidek, Vaclav Papousek, Frantisek Kolar, Frantisek Cardona, Maria Ruiz-Meana, Marisol García-Dorado, David Comella, Joan X Felkin, Leanne E Barton, Paul JR Arany, Zoltan Pravenec, Michal Petretto, Enrico Sanchis, Daniel Cook, Stuart A. |
| author_sort |
McDermott-Roe, Chris |
| title |
Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function |
| title_short |
Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function |
| title_full |
Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function |
| title_fullStr |
Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function |
| title_full_unstemmed |
Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function |
| title_sort |
endonuclease g is a novel determinant of cardiac hypertrophy and mitochondrial function |
| description |
Left ventricular mass (LVM) is a highly heritable trait1 and an independent risk factor for all-cause mortality2. To date, genome-wide association studies (GWASs) have not identified the genetic factors underlying LVM variation3 and the regulatory mechanisms for blood pressure (BP)-independent cardiac hypertrophy remain poorly understood4,5. Unbiased systems-genetics approaches in the rat6,7 now provide a powerful complementary tool to GWAS and we applied integrative genomics to dissect a highly replicated, BP-independent LVM locus on rat chromosome 3p. We identified endonuclease G (Endog), previously implicated in apoptosis8 but not hypertrophy, as the gene at the locus and demonstrated loss-of-function mutation in Endog 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 inferred ENDOG in fundamental mitochondrial processes unrelated to apoptosis. We showed direct regulation of ENDOG by ERRα and PGC1α, master regulators of mitochondrial and cardiac function9,10,11, interaction of ENDOG with the mitochondrial genome and ENDOG-mediated regulation of mitochondrial mass. At baseline, Endog deleted mouse heart had depleted mitochondria, mitochondrial dysfunction and elevated reactive oxygen species (ROS), which was associated with enlarged and steatotic cardiomyocytes. Our studies establish further the link between mitochondrial dysfunction, ROS and heart disease and demonstrate a new role for Endog in maladaptive cardiac hypertrophy. |
| publishDate |
2011 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3189541/ |
| _version_ |
1611479691661672448 |