Investigating the Therapeutic Potential of Cdk8 Small Molecule Inhibitors to Prevent Pathological Cardiac Remodeling and Heart Failure.

Pathological cardiac hypertrophy represents a major risk factor for heart failure (HF). Cardiac hypertrophic responses are coordinated in part through altered transcriptional dynamics involving chromatin structure and accessibility, transcription factor (TF) activation, and enhancer utilization. Mediator is a multiprotein complex that integrates signal-dependent TFs with basal transcriptional machinery to regulate downstream gene expression. Cyclin-dependent kinase 8 (Cdk8) is a Mediator kinase demonstrated to have a complex role in transcription regulation, driving both transcription activation and inhibition in context-specific ways. Previous studies have demonstrated that Cdk8 protein expression is increased in human and mouse HF. Cardiomyocyte-specific Cdk8 overexpression leads to eccentric cardiac hypertrophy consistent with HF, suggesting that Cdk8 activity may play a significant role in the progression of HF. To investigate the therapeutic potential in regulating Cdk8 activity, we used Cdk8 selective inhibitors SenexinA and CCT251545 in an in vitro neonatal rat cardiomyocyte hypertrophy model, resulting in altered regulation of hypertrophic transcriptional programs and blunted cardiomyocyte hypertrophy. To further assess Cdk8 kinase activity in regulating hypertrophic responses, Cdk8 inhibitor CCT251545 was used in an in vivo angiotensin II-induced hypertensive mouse model. It was hypothesized that Cdk8 inhibition by CCT251545 in vivo would lead to reduced hypertrophic responses. Results indicate that CCT251545 is effective at inhibiting Cdk8 activity, leading to blunted hypertrophic responses with altered gene expression. These studies demonstrate a role for Cdk8 activity in transcriptional regulation of genes associated with pathological cardiac hypertrophy, which can ultimately lead to heart failure.