Abstract Body: Background: Maintenance of cardiomyocyte homeostasis is essential for preserving long-term cardiac function and preventing heart failure. The Mediator complex plays an essential role by coordinating signal-dependent transcriptional programs which regulate cardiac gene expression. We and others have demonstrated the role of the mediator complex kinase submodule in preserving basal cardiac function, however the role of Cyclin Dependent Kinase 8 (Cdk8) within this complex remains undefined in cardiomyocytes. We hypothesized that cardiomyocyte-specific loss of Cdk8 would compromise transcriptional regulation required for normal cardiac function, leading to heart failure and early lethality.
Methods: To determine Cdk8’s role in cardiomyocytes, we generated a cardiomyocyte specific knockout mouse model using Myh6 Cre. Male mice were evaluated by serial echocardiography at 3, 6, and 9 months of age to measure cardiac function. Survival was assessed by Kaplan - Meier analysis. Transcriptomic and histological analyses are ongoing to define the molecular consequences of Cdk8 deletion.
Results: Cardiomyocyte-specific deletion of Cdk8 resulted in progressive systolic dysfunction. Left ventricular ejection fraction was preserved in knockout mice compared to controls at 3 months (0.745 ± 0.028 vs 0.799 ± 0.013, n= 11, p< 0.1184). However, at 6 months of age, knockout mice demonstrated a substantial decline in ejection fraction compared to controls (0.550 ± 0.028 vs 0.745 ± 0.015, n=11, p<0.0001) consistent with overt systolic dysfunction. Preliminary Kaplan–Meier analysis suggests reduced survival in cardiomyocyte-specific Cdk8 knockout mice, with deaths beginning around 8 months of age. Survival monitoring is ongoing.
Conclusions: These findings identify Cdk8 as a critical regulator of cardiomyocyte function. Loss of Cdk8 results in progressive systolic dysfunction, pathological remodeling, and premature mortality. Ongoing transcriptomic studies will define the gene networks regulated by Cdk8, while future work will determine the mechanisms necessary for preservation of cardiac homeostasis.