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

Yuzhi Jia, Ning Liu, Navin Viswakarma, Ruya Sun, Mathew J. Schipma, Meng Shang, Edward B. Thorp, Yashpal S. Kanwar, Bayar Thimmapaya*, Janardan K. Reddy

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Scopus citations

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
Publication statusPublished - May 16 2018

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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

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