Abstract
Abstract 585: CDK8 Activity-dependent Regulation of Heart Disease
Circulation research, Vol.123(Suppl_1)
08/03/2018
DOI: 10.1161/res.123.suppl_1.585
Abstract
Pathological cardiac hypertrophy represents a major risk factor for heart failure (HF). The hypertrophic response is orchestrated in part through transcriptional alterations that ultimately modify cardiac function. Mediator is a multiprotein complex that coordinates signal dependent transcription factors with basal transcriptional machinery including RNA polymerase II and general transcription factors. Transcriptional regulation by Mediator complex can be modified by the association of the Mediator complex kinase submodule with the core complex. Cyclin-dependent kinase 8 (CDK8) is a kinase present in the submodule that has been demonstrated to have a complex role in transcriptional regulation through a number of mechanisms involving both transcriptional activation and inhibition. Our lab has demonstrated that CDK8 expression is upregulated in murine HF models as well as in failing human hearts. In addition, cardiac CDK8 over-expression promotes transcriptional remodeling that results in dilated cardiomyopathy suggesting that CDK8 inhibition may represent a novel pharmacological target. This study utilizes CDK8 kinase inhibitor, Senexin A, which is being evaluated as an anti-cancer chemotherapeutic agent. Here, we demonstrate that Senexin A inhibits kinase activity in an
in vitro
neonatal rat cardiomyocyte (NRCM) model resulting in reduced cardiomyocyte hypertrophy as well as a reduction in expression of specific cardiomyocyte hypertrophy markers. These studies demonstrate a role for CDK8 activity in transcriptional regulation of genes associated with pathological cardiac remodeling that drives cardiac hypertrophy and ultimately HF.
Details
- Title: Subtitle
- Abstract 585: CDK8 Activity-dependent Regulation of Heart Disease
- Creators
- Rachel Minerath - University of IowaAllison Vaske - University of IowaDuane Hall - University of IowaChad Grueter - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Circulation research, Vol.123(Suppl_1)
- DOI
- 10.1161/res.123.suppl_1.585
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Language
- English
- Date published
- 08/03/2018
- Academic Unit
- Cardiovascular Medicine; Craniofacial Anomalies Research Center; Internal Medicine
- Record Identifier
- 9984362738602771
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