Class I HDACs control a JIP1-dependent pathway for kinesin-microtubule binding in cardiomyocytes

Area of Science:

• Cardiology
• Molecular Biology
• Cell Biology

Background:

• Class I histone deacetylase (HDAC) inhibitors are known to prevent cardiac hypertrophy and fibrosis.
• The effects of HDAC inhibition on unstressed cardiac cells are not well understood.

Purpose of the Study:

• To investigate the impact of HDAC inhibition on cardiomyocyte signaling and gene expression in unstressed conditions.
• To elucidate the role of induced c-Jun amino-terminal kinase (JNK)-interacting protein-1 (JIP1) in cardiomyocytes following HDAC inhibition.

Main Methods:

• Treatment of cultured cardiomyocytes with small molecule Class I HDAC inhibitors.
• Analysis of JIP1 and KIF5A mRNA and protein expression.
• Assessment of JNK signaling pathways and cardiomyocyte hypertrophy.
• Investigation of JIP1:KIF5A:microtubule complex formation and intracellular transport.

Main Results:

• HDAC inhibitors significantly induced JIP1 mRNA and protein expression in cardiomyocytes.
• Elevated JIP1 levels did not alter JNK signaling or cardiomyocyte hypertrophy.
• HDAC inhibitor-induced JIP1 was essential for stimulating KIF5A expression.
• A novel HDAC-dependent regulatory circuit involving JIP1:KIF5A:microtubule complexes was identified, regulating intracellular transport of cargo like autophagosomes.

Conclusions:

• Class I HDACs play a novel role in controlling the JIP1/kinesin axis in cardiomyocytes.
• HDAC inhibitors can modulate microtubule transport in the heart via this pathway.
• This discovery suggests potential therapeutic applications for HDAC inhibitors in altering cardiac intracellular transport.