Cdk19-dependent transcriptional mechanisms in cardiac hypertrophy

项目总结/文摘

Project Summary/Abstract Heart failure due to chronic hypertension continues to significantly impact human health despite long term management with current treatments. This is in part due to the many unknown factors that underlie the development of hypertensive heart failure. Research in animal models has demonstrated activation of pathological gene expression in heart failure suggesting a causal relationship. The objective of this proposal is to determine how Cdk19 (and Cdk8) activity and association with Mediator regulates cardiac gene expression, left ventricular hypertrophy, and left ventricular dysfunction during hypertensive pressure overload stress in mice using transaortic banding (TAB) or Ang-II treatment. It is our hypothesis, that Cdk19 activity is necessary for the complete hypertensive HF functional response through Mediator-dependent transcriptional regulation. The specific Aims designed to test this hypothesis using a combination of genetically modified mice and pharmacological inhibitors are: Aim 1. Determine the requirement for Cdk8/19 activity in cardiomyocyte hypertrophic and hypertensive responses. It is our working hypothesis that the activity of Cdk8/19 drives hypertensive HF responses. Based on our preliminary data, we predict that in vivo inhibition of endogenous Cdk8/19 activity with CCT251545 and Senexin A will blunt both LVH after TAB and Ang-II treatment reducing hypertrophic cardiac remodeling. To address the structural role of Cdk8 and Cdk19, we developed Aim 2. Determine the impact of Cdk8/19 on the physiological and biochemical actions of cardiomyocytes that are necessary for normal cardiac function. Our working hypothesis is that loss of Cdk8/19 results in cardiomyocyte dysfunction due to dysregulated enhancer utilization and gene expression. Due to the potential redundant roles of Cdk8 and Cdk19, we don’t anticipate cardiac knockout of either Cdk8 (Cdk8-cKO) or Cdk19 (Cdk19-KO) alone will block left ventricular hypertrophy or transcriptional remodeling. However, we propose the double knockout of Cdk8/19 will be required due to the role of Cdk8/19 in Mediator localization to stress-responsive enhancers in stressed hearts. The outcomes of this proposal will establish potential therapeutic targets for modifying transcriptional programing in response to hypertension and heart failure.