Journal article
Ectopic expression of Cdk8 induces eccentric hypertrophy and heart failure
JCI insight, Vol.2(15), e92476
08/03/2017
DOI: 10.1172/jci.insight.92476
PMCID: PMC5543923
PMID: 28768905
Abstract
Widespread changes in cardiac gene expression occur during heart failure, yet the mechanisms responsible for coordinating these changes remain poorly understood. The Mediator complex represents a nodal point for modulating transcription by bridging chromatin-bound transcription factors with RNA polymerase II activity; it is reversibly regulated by its cyclin-dependent kinase 8 (Cdk8) kinase submodule. Here, we identified increased Cdk8 protein expression in human failing heart explants and determined the consequence of this increase in cardiac-specific Cdk8-expressing mice. Transgenic Cdk8 overexpression resulted in progressive dilated cardiomyopathy, heart failure, and premature lethality. Prior to functional decline, left ventricular cardiomyocytes were dramatically elongated, with disorganized transverse tubules and dysfunctional calcium handling. RNA sequencing results showed that myofilament gene isoforms not typically expressed in adult cardiomyocytes were enriched, while oxidative phosphorylation and fatty acid biosynthesis genes were downregulated. Interestingly, candidate upstream transcription factor expression levels and MAPK signaling pathways thought to determine cardiomyocyte size remained relatively unaffected, suggesting that Cdk8 functions within a novel growth regulatory pathway. Our findings show that manipulating cardiac gene expression through increased Cdk8 levels is detrimental to the heart by establishing a transcriptional program that induces pathological remodeling and eccentric hypertrophy culminating in heart failure.
Manipulating cardiac gene expression through increased Cdk8 levels is detrimental to the heart by establishing a transcriptional program that induces pathological remodeling and hypertrophy.
Details
- Title: Subtitle
- Ectopic expression of Cdk8 induces eccentric hypertrophy and heart failure
- Creators
- Duane D Hall - Department of Internal Medicine, Division of Cardiovascular Medicine, Francois M. Abboud Cardiovascular Research Center, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, USAJessica M Ponce - Department of Internal Medicine, Division of Cardiovascular Medicine, Francois M. Abboud Cardiovascular Research Center, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, USABiyi Chen - Department of Internal Medicine, Division of Cardiovascular Medicine, Francois M. Abboud Cardiovascular Research Center, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, USAKathryn M Spitler - Department of Internal Medicine, Division of Cardiovascular Medicine, Francois M. Abboud Cardiovascular Research Center, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, USAAdrianne Alexia - Department of Internal Medicine, Division of Cardiovascular Medicine, Francois M. Abboud Cardiovascular Research Center, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, USAGavin Y Oudit - Department of Medicine, University of Alberta, Edmonton, Alberta, CanadaLong-Sheng Song - Department of Internal Medicine, Division of Cardiovascular Medicine, Francois M. Abboud Cardiovascular Research Center, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, USAChad E Grueter - Department of Internal Medicine, Division of Cardiovascular Medicine, Francois M. Abboud Cardiovascular Research Center, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, USA
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.2(15), e92476
- DOI
- 10.1172/jci.insight.92476
- PMID
- 28768905
- PMCID
- PMC5543923
- NLM abbreviation
- JCI Insight
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Publisher
- American Society for Clinical Investigation
- Language
- English
- Date published
- 08/03/2017
- Academic Unit
- Cardiovascular Medicine; Craniofacial Anomalies Research Center; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Health, Sport, and Human Physiology ; Internal Medicine
- Record Identifier
- 9984094352302771
Metrics
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