PIMT/NCOA6IP deletion in the mouse heart causes delayed cardiomyopathy attributable to perturbation in energy metabolism

Yuzhi Jia, Ning Liu, Navin Viswakarma, Ruya Sun, Matthew John Schipma, Meng Shang, Edward Benjamin Thorp, Yashpal S Kanwar, Bayar Thimmapaya*, Janardan K Reddy

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

PIMT/NCOA6IP, a transcriptional coactivator PRIP/NCOA6 binding protein, enhances nuclear receptor transcriptional activity. Germline disruption of PIMT results in early embryonic lethality due to impairment of development around blastocyst and uterine implantation stages. We now generated mice with Cre-mediated cardiac-specific deletion of PIMT (csPIMT −/− ) in adult mice. These mice manifest enlargement of heart, with nearly 100% mortality by 7.5 months of age due to dilated cardiomyopathy. Significant reductions in the expression of genes (i) pertaining to mitochondrial respiratory chain complexes I to IV; (ii) calcium cycling cardiac muscle contraction (Atp2a1, Atp2a2, Ryr2); and (iii) nuclear receptor PPAR- regulated genes involved in glucose and fatty acid energy metabolism were found in csPIMT −/− mouse heart. Elevated levels of Nppa and Nppb mRNAs were noted in csPIMT −/− heart indicative of myocardial damage. These hearts revealed increased reparative fibrosis associated with enhanced expression of Tgfβ2 and Ctgf. Furthermore, cardiac-specific deletion of PIMT in adult mice, using tamoxifen-inducible Cre-approach (TmcsPIMT −/− ), results in the development of cardiomyopathy. Thus, cumulative evidence suggests that PIMT functions in cardiac energy metabolism by interacting with nuclear receptor coactivators and this property could be useful in the management of heart failure.

Original languageEnglish (US)
Article number1485
JournalInternational journal of molecular sciences
Volume19
Issue number5
DOIs
StatePublished - May 16 2018

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deletion
metabolism
Cardiomyopathies
Energy Metabolism
mice
perturbation
causes
Cytoplasmic and Nuclear Receptors
genes
Nuclear Receptor Coactivators
Genes
muscular function
energy
Electron Transport Complex I
lethality
fibrosis
Ryanodine Receptor Calcium Release Channel
Peroxisome Proliferator-Activated Receptors
mortality
impairment

Keywords

  • Cardiac fibrosis
  • Dilated cardiomyopathy
  • Energy metabolism
  • PIMT/NCOA6IP
  • PPARα
  • PRIP/NCOA6

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

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title = "PIMT/NCOA6IP deletion in the mouse heart causes delayed cardiomyopathy attributable to perturbation in energy metabolism",
abstract = "PIMT/NCOA6IP, a transcriptional coactivator PRIP/NCOA6 binding protein, enhances nuclear receptor transcriptional activity. Germline disruption of PIMT results in early embryonic lethality due to impairment of development around blastocyst and uterine implantation stages. We now generated mice with Cre-mediated cardiac-specific deletion of PIMT (csPIMT −/− ) in adult mice. These mice manifest enlargement of heart, with nearly 100{\%} mortality by 7.5 months of age due to dilated cardiomyopathy. Significant reductions in the expression of genes (i) pertaining to mitochondrial respiratory chain complexes I to IV; (ii) calcium cycling cardiac muscle contraction (Atp2a1, Atp2a2, Ryr2); and (iii) nuclear receptor PPAR- regulated genes involved in glucose and fatty acid energy metabolism were found in csPIMT −/− mouse heart. Elevated levels of Nppa and Nppb mRNAs were noted in csPIMT −/− heart indicative of myocardial damage. These hearts revealed increased reparative fibrosis associated with enhanced expression of Tgfβ2 and Ctgf. Furthermore, cardiac-specific deletion of PIMT in adult mice, using tamoxifen-inducible Cre-approach (TmcsPIMT −/− ), results in the development of cardiomyopathy. Thus, cumulative evidence suggests that PIMT functions in cardiac energy metabolism by interacting with nuclear receptor coactivators and this property could be useful in the management of heart failure.",
keywords = "Cardiac fibrosis, Dilated cardiomyopathy, Energy metabolism, PIMT/NCOA6IP, PPARα, PRIP/NCOA6",
author = "Yuzhi Jia and Ning Liu and Navin Viswakarma and Ruya Sun and Schipma, {Matthew John} and Meng Shang and Thorp, {Edward Benjamin} and Kanwar, {Yashpal S} and Bayar Thimmapaya and Reddy, {Janardan K}",
year = "2018",
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language = "English (US)",
volume = "19",
journal = "International Journal of Molecular Sciences",
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T1 - PIMT/NCOA6IP deletion in the mouse heart causes delayed cardiomyopathy attributable to perturbation in energy metabolism

AU - Jia, Yuzhi

AU - Liu, Ning

AU - Viswakarma, Navin

AU - Sun, Ruya

AU - Schipma, Matthew John

AU - Shang, Meng

AU - Thorp, Edward Benjamin

AU - Kanwar, Yashpal S

AU - Thimmapaya, Bayar

AU - Reddy, Janardan K

PY - 2018/5/16

Y1 - 2018/5/16

N2 - PIMT/NCOA6IP, a transcriptional coactivator PRIP/NCOA6 binding protein, enhances nuclear receptor transcriptional activity. Germline disruption of PIMT results in early embryonic lethality due to impairment of development around blastocyst and uterine implantation stages. We now generated mice with Cre-mediated cardiac-specific deletion of PIMT (csPIMT −/− ) in adult mice. These mice manifest enlargement of heart, with nearly 100% mortality by 7.5 months of age due to dilated cardiomyopathy. Significant reductions in the expression of genes (i) pertaining to mitochondrial respiratory chain complexes I to IV; (ii) calcium cycling cardiac muscle contraction (Atp2a1, Atp2a2, Ryr2); and (iii) nuclear receptor PPAR- regulated genes involved in glucose and fatty acid energy metabolism were found in csPIMT −/− mouse heart. Elevated levels of Nppa and Nppb mRNAs were noted in csPIMT −/− heart indicative of myocardial damage. These hearts revealed increased reparative fibrosis associated with enhanced expression of Tgfβ2 and Ctgf. Furthermore, cardiac-specific deletion of PIMT in adult mice, using tamoxifen-inducible Cre-approach (TmcsPIMT −/− ), results in the development of cardiomyopathy. Thus, cumulative evidence suggests that PIMT functions in cardiac energy metabolism by interacting with nuclear receptor coactivators and this property could be useful in the management of heart failure.

AB - PIMT/NCOA6IP, a transcriptional coactivator PRIP/NCOA6 binding protein, enhances nuclear receptor transcriptional activity. Germline disruption of PIMT results in early embryonic lethality due to impairment of development around blastocyst and uterine implantation stages. We now generated mice with Cre-mediated cardiac-specific deletion of PIMT (csPIMT −/− ) in adult mice. These mice manifest enlargement of heart, with nearly 100% mortality by 7.5 months of age due to dilated cardiomyopathy. Significant reductions in the expression of genes (i) pertaining to mitochondrial respiratory chain complexes I to IV; (ii) calcium cycling cardiac muscle contraction (Atp2a1, Atp2a2, Ryr2); and (iii) nuclear receptor PPAR- regulated genes involved in glucose and fatty acid energy metabolism were found in csPIMT −/− mouse heart. Elevated levels of Nppa and Nppb mRNAs were noted in csPIMT −/− heart indicative of myocardial damage. These hearts revealed increased reparative fibrosis associated with enhanced expression of Tgfβ2 and Ctgf. Furthermore, cardiac-specific deletion of PIMT in adult mice, using tamoxifen-inducible Cre-approach (TmcsPIMT −/− ), results in the development of cardiomyopathy. Thus, cumulative evidence suggests that PIMT functions in cardiac energy metabolism by interacting with nuclear receptor coactivators and this property could be useful in the management of heart failure.

KW - Cardiac fibrosis

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KW - Energy metabolism

KW - PIMT/NCOA6IP

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