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PIMT/NCOA6IP Deletion in the Mouse Heart Causes Delayed Cardiomyopathy Attributable to Perturbation in Energy Metabolism

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...

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Autores principales: Jia, Yuzhi, Liu, Ning, Viswakarma, Navin, Sun, Ruya, Schipma, Mathew J., Shang, Meng, Thorp, Edward B., Kanwar, Yashpal S., Thimmapaya, Bayar, Reddy, Janardan K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983783/
https://www.ncbi.nlm.nih.gov/pubmed/29772707
http://dx.doi.org/10.3390/ijms19051485
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author Jia, Yuzhi
Liu, Ning
Viswakarma, Navin
Sun, Ruya
Schipma, Mathew J.
Shang, Meng
Thorp, Edward B.
Kanwar, Yashpal S.
Thimmapaya, Bayar
Reddy, Janardan K.
author_facet Jia, Yuzhi
Liu, Ning
Viswakarma, Navin
Sun, Ruya
Schipma, Mathew J.
Shang, Meng
Thorp, Edward B.
Kanwar, Yashpal S.
Thimmapaya, Bayar
Reddy, Janardan K.
author_sort Jia, Yuzhi
collection PubMed
description 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.
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spelling pubmed-59837832018-06-05 PIMT/NCOA6IP Deletion in the Mouse Heart Causes Delayed Cardiomyopathy Attributable to Perturbation in Energy Metabolism Jia, Yuzhi Liu, Ning Viswakarma, Navin Sun, Ruya Schipma, Mathew J. Shang, Meng Thorp, Edward B. Kanwar, Yashpal S. Thimmapaya, Bayar Reddy, Janardan K. Int J Mol Sci Article 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. MDPI 2018-05-16 /pmc/articles/PMC5983783/ /pubmed/29772707 http://dx.doi.org/10.3390/ijms19051485 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Jia, Yuzhi
Liu, Ning
Viswakarma, Navin
Sun, Ruya
Schipma, Mathew J.
Shang, Meng
Thorp, Edward B.
Kanwar, Yashpal S.
Thimmapaya, Bayar
Reddy, Janardan K.
PIMT/NCOA6IP Deletion in the Mouse Heart Causes Delayed Cardiomyopathy Attributable to Perturbation in Energy Metabolism
title PIMT/NCOA6IP Deletion in the Mouse Heart Causes Delayed Cardiomyopathy Attributable to Perturbation in Energy Metabolism
title_full PIMT/NCOA6IP Deletion in the Mouse Heart Causes Delayed Cardiomyopathy Attributable to Perturbation in Energy Metabolism
title_fullStr PIMT/NCOA6IP Deletion in the Mouse Heart Causes Delayed Cardiomyopathy Attributable to Perturbation in Energy Metabolism
title_full_unstemmed PIMT/NCOA6IP Deletion in the Mouse Heart Causes Delayed Cardiomyopathy Attributable to Perturbation in Energy Metabolism
title_short PIMT/NCOA6IP Deletion in the Mouse Heart Causes Delayed Cardiomyopathy Attributable to Perturbation in Energy Metabolism
title_sort pimt/ncoa6ip deletion in the mouse heart causes delayed cardiomyopathy attributable to perturbation in energy metabolism
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983783/
https://www.ncbi.nlm.nih.gov/pubmed/29772707
http://dx.doi.org/10.3390/ijms19051485
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