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Cardiomyocyte-Specific Ablation of Med1 Subunit of the Mediator Complex Causes Lethal Dilated Cardiomyopathy in Mice

Mediator, an evolutionarily conserved multi-protein complex consisting of about 30 subunits, is a key component of the polymerase II mediated gene transcription. Germline deletion of the Mediator subunit 1 (Med1) of the Mediator in mice results in mid-gestational embryonic lethality with development...

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Autores principales: Jia, Yuzhi, Chang, Hsiang-Chun, Schipma, Matthew J., Liu, Jing, Shete, Varsha, Liu, Ning, Sato, Tatsuya, Thorp, Edward B., Barger, Philip M., Zhu, Yi-Jun, Viswakarma, Navin, Kanwar, Yashpal S., Ardehali, Hossein, Thimmapaya, Bayar, Reddy, Janardan K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4993490/
https://www.ncbi.nlm.nih.gov/pubmed/27548259
http://dx.doi.org/10.1371/journal.pone.0160755
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author Jia, Yuzhi
Chang, Hsiang-Chun
Schipma, Matthew J.
Liu, Jing
Shete, Varsha
Liu, Ning
Sato, Tatsuya
Thorp, Edward B.
Barger, Philip M.
Zhu, Yi-Jun
Viswakarma, Navin
Kanwar, Yashpal S.
Ardehali, Hossein
Thimmapaya, Bayar
Reddy, Janardan K.
author_facet Jia, Yuzhi
Chang, Hsiang-Chun
Schipma, Matthew J.
Liu, Jing
Shete, Varsha
Liu, Ning
Sato, Tatsuya
Thorp, Edward B.
Barger, Philip M.
Zhu, Yi-Jun
Viswakarma, Navin
Kanwar, Yashpal S.
Ardehali, Hossein
Thimmapaya, Bayar
Reddy, Janardan K.
author_sort Jia, Yuzhi
collection PubMed
description Mediator, an evolutionarily conserved multi-protein complex consisting of about 30 subunits, is a key component of the polymerase II mediated gene transcription. Germline deletion of the Mediator subunit 1 (Med1) of the Mediator in mice results in mid-gestational embryonic lethality with developmental impairment of multiple organs including heart. Here we show that cardiomyocyte-specific deletion of Med1 in mice (csMed1(-/-)) during late gestational and early postnatal development by intercrossing Med1(fl/fl) mice to α-MyHC-Cre transgenic mice results in lethality within 10 days after weaning due to dilated cardiomyopathy-related ventricular dilation and heart failure. The csMed1(-/-) mouse heart manifests mitochondrial damage, increased apoptosis and interstitial fibrosis. Global gene expression analysis revealed that loss of Med1 in heart down-regulates more than 200 genes including Acadm, Cacna1s, Atp2a2, Ryr2, Pde1c, Pln, PGC1α, and PGC1β that are critical for calcium signaling, cardiac muscle contraction, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy and peroxisome proliferator-activated receptor regulated energy metabolism. Many genes essential for oxidative phosphorylation and proper mitochondrial function such as genes coding for the succinate dehydrogenase subunits of the mitochondrial complex II are also down-regulated in csMed1(-/-) heart contributing to myocardial injury. Data also showed up-regulation of about 180 genes including Tgfb2, Ace, Atf3, Ctgf, Angpt14, Col9a2, Wisp2, Nppa, Nppb, and Actn1 that are linked to cardiac muscle contraction, cardiac hypertrophy, cardiac fibrosis and myocardial injury. Furthermore, we demonstrate that cardiac specific deletion of Med1 in adult mice using tamoxifen-inducible Cre approach (TmcsMed1(-/-)), results in rapid development of cardiomyopathy and death within 4 weeks. We found that the key findings of the csMed1(-/-) studies described above are highly reproducible in TmcsMed1(-/-) mouse heart. Collectively, these observations suggest that Med1 plays a critical role in the maintenance of heart function impacting on multiple metabolic, compensatory and reparative pathways with a likely therapeutic potential in the management of heart failure.
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spelling pubmed-49934902016-09-12 Cardiomyocyte-Specific Ablation of Med1 Subunit of the Mediator Complex Causes Lethal Dilated Cardiomyopathy in Mice Jia, Yuzhi Chang, Hsiang-Chun Schipma, Matthew J. Liu, Jing Shete, Varsha Liu, Ning Sato, Tatsuya Thorp, Edward B. Barger, Philip M. Zhu, Yi-Jun Viswakarma, Navin Kanwar, Yashpal S. Ardehali, Hossein Thimmapaya, Bayar Reddy, Janardan K. PLoS One Research Article Mediator, an evolutionarily conserved multi-protein complex consisting of about 30 subunits, is a key component of the polymerase II mediated gene transcription. Germline deletion of the Mediator subunit 1 (Med1) of the Mediator in mice results in mid-gestational embryonic lethality with developmental impairment of multiple organs including heart. Here we show that cardiomyocyte-specific deletion of Med1 in mice (csMed1(-/-)) during late gestational and early postnatal development by intercrossing Med1(fl/fl) mice to α-MyHC-Cre transgenic mice results in lethality within 10 days after weaning due to dilated cardiomyopathy-related ventricular dilation and heart failure. The csMed1(-/-) mouse heart manifests mitochondrial damage, increased apoptosis and interstitial fibrosis. Global gene expression analysis revealed that loss of Med1 in heart down-regulates more than 200 genes including Acadm, Cacna1s, Atp2a2, Ryr2, Pde1c, Pln, PGC1α, and PGC1β that are critical for calcium signaling, cardiac muscle contraction, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy and peroxisome proliferator-activated receptor regulated energy metabolism. Many genes essential for oxidative phosphorylation and proper mitochondrial function such as genes coding for the succinate dehydrogenase subunits of the mitochondrial complex II are also down-regulated in csMed1(-/-) heart contributing to myocardial injury. Data also showed up-regulation of about 180 genes including Tgfb2, Ace, Atf3, Ctgf, Angpt14, Col9a2, Wisp2, Nppa, Nppb, and Actn1 that are linked to cardiac muscle contraction, cardiac hypertrophy, cardiac fibrosis and myocardial injury. Furthermore, we demonstrate that cardiac specific deletion of Med1 in adult mice using tamoxifen-inducible Cre approach (TmcsMed1(-/-)), results in rapid development of cardiomyopathy and death within 4 weeks. We found that the key findings of the csMed1(-/-) studies described above are highly reproducible in TmcsMed1(-/-) mouse heart. Collectively, these observations suggest that Med1 plays a critical role in the maintenance of heart function impacting on multiple metabolic, compensatory and reparative pathways with a likely therapeutic potential in the management of heart failure. Public Library of Science 2016-08-22 /pmc/articles/PMC4993490/ /pubmed/27548259 http://dx.doi.org/10.1371/journal.pone.0160755 Text en © 2016 Jia et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Jia, Yuzhi
Chang, Hsiang-Chun
Schipma, Matthew J.
Liu, Jing
Shete, Varsha
Liu, Ning
Sato, Tatsuya
Thorp, Edward B.
Barger, Philip M.
Zhu, Yi-Jun
Viswakarma, Navin
Kanwar, Yashpal S.
Ardehali, Hossein
Thimmapaya, Bayar
Reddy, Janardan K.
Cardiomyocyte-Specific Ablation of Med1 Subunit of the Mediator Complex Causes Lethal Dilated Cardiomyopathy in Mice
title Cardiomyocyte-Specific Ablation of Med1 Subunit of the Mediator Complex Causes Lethal Dilated Cardiomyopathy in Mice
title_full Cardiomyocyte-Specific Ablation of Med1 Subunit of the Mediator Complex Causes Lethal Dilated Cardiomyopathy in Mice
title_fullStr Cardiomyocyte-Specific Ablation of Med1 Subunit of the Mediator Complex Causes Lethal Dilated Cardiomyopathy in Mice
title_full_unstemmed Cardiomyocyte-Specific Ablation of Med1 Subunit of the Mediator Complex Causes Lethal Dilated Cardiomyopathy in Mice
title_short Cardiomyocyte-Specific Ablation of Med1 Subunit of the Mediator Complex Causes Lethal Dilated Cardiomyopathy in Mice
title_sort cardiomyocyte-specific ablation of med1 subunit of the mediator complex causes lethal dilated cardiomyopathy in mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4993490/
https://www.ncbi.nlm.nih.gov/pubmed/27548259
http://dx.doi.org/10.1371/journal.pone.0160755
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