DNA Damage and Nuclear Morphological Changes in Cardiac Hypertrophy Are Mediated by SNRK Through Actin...

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Cellular Biology

Background:

• Proper nuclear organization is essential for cardiomyocyte function; nuclear structural remodeling is implicated in cardiovascular disease.
• DNA damage has been linked to cardiac hypertrophy, but the underlying mechanisms remain unclear.
• AMP-activated protein kinase (AMPK) family members regulate metabolism and DNA damage response (DDR).

Purpose of the Study:

• To investigate the role of SNF1-related kinase (SNRK) in cardiac hypertrophy and DNA damage response (DDR).
• To determine if SNRK influences cardiomyocyte nuclear structure and function.
• To identify SNRK's molecular targets and interaction partners involved in cardiac remodeling.

Main Methods:

• Cardiac-specific Snrk knockout mice underwent transaortic banding to assess cardiac function and DDR.
• In vitro studies modulated SNRK expression to evaluate effects on DDR and nuclear parameters.
• Phosphoproteomics identified SNRK targets, and coimmunoprecipitation confirmed Destrin (DSTN) as a binding partner.

Main Results:

• Snrk knockout mice exhibited worsened cardiac function, increased hypertrophy, and elevated DDR marker pH2AX.
• In vitro Snrk knockdown led to increased DNA damage, chromatin compaction, and altered nuclear morphology.
• SNRK phosphorylates DSTN, and their interaction regulates actin polymerization, impacting DNA damage and nuclear shape.

Conclusions:

• SNRK plays a critical role in cardiac hypertrophy and DNA damage via its interaction with DSTN.
• This interaction modulates actin polymerization, thereby influencing DNA damage response and cardiomyocyte nuclear integrity.
• Targeting the SNRK-DSTN pathway may offer therapeutic strategies for cardiovascular diseases involving nuclear abnormalities.