Ectopic expression of Cdk8 induces eccentric hypertrophy and heart failure

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Gene Regulation

Background:

• Heart failure involves widespread cardiac gene expression changes.
• The Mediator complex, regulated by cyclin-dependent kinase 8 (Cdk8), coordinates transcription.
• Mechanisms controlling these cardiac gene expression changes are poorly understood.

Purpose of the Study:

• To investigate the role of increased Cdk8 protein expression in human heart failure.
• To determine the consequences of cardiac-specific Cdk8 overexpression in mice.

Main Methods:

• Analysis of human failing heart explants for Cdk8 protein levels.
• Generation and analysis of cardiac-specific Cdk8-overexpressing transgenic mice.
• RNA sequencing to assess cardiac gene expression changes.
• Assessment of cardiomyocyte structure, calcium handling, and cardiac function.

Main Results:

• Human failing hearts showed increased Cdk8 protein.
• Transgenic mice with cardiac Cdk8 overexpression developed dilated cardiomyopathy, heart failure, and premature death.
• Cardiomyocytes exhibited elongation, disorganized transverse tubules, and impaired calcium handling.
• RNA sequencing revealed enrichment of non-adult myofilament gene isoforms and downregulation of oxidative phosphorylation and fatty acid biosynthesis genes.
• Key upstream transcription factors and MAPK pathways were unaffected, suggesting a novel regulatory pathway.

Conclusions:

• Elevated Cdk8 levels in the heart are detrimental, causing pathological remodeling and heart failure.
• Cdk8 overexpression establishes a transcriptional program leading to eccentric hypertrophy.
• Cdk8 represents a potential therapeutic target in heart failure.