Downregulation of HHATL promotes cardiac hypertrophy via activation of SHH/DRP1

Area of Science:

• Cardiovascular Biology
• Genetics
• Mitochondrial Biology

Background:

• HHATL is a prioritized gene for hypertrophic cardiomyopathy (HCM).
• Previous studies linked HHATL to cardiac hypertrophy in zebrafish.
• The precise mechanisms of HHATL in cardiac hypertrophy were unclear.

Purpose of the Study:

• To elucidate the pathogenic mechanisms of HHATL in cardiac hypertrophy.
• To investigate the role of HHATL in the SHH/DRP1 signaling pathway.
• To explore HHATL as a potential therapeutic target for HCM.

Main Methods:

• Analyzing HHATL mutations in nonsarcomeric HCM patients.
• Assessing HHATL expression in human HCM tissues and a mouse model.
• Utilizing H9C2 cell lines to study HHATL downregulation effects.
• Investigating the impact of SHH signaling and DRP1 levels.
• Employing SHH inhibitor (RU-SKI 43) and DRP1 overexpression for intervention.

Main Results:

• Six rare HHATL mutations were found in 6.94% of nonsarcomeric HCM patients.
• HHATL expression decreased in HCM patient hearts and a cardiac hypertrophy mouse model.
• HHATL downregulation in H9C2 cells increased hypertrophic markers and ROS, causing cardiac hypertrophy and mitochondrial dysfunction.
• SHH signaling (SHHN) increased, while DRP1 levels decreased upon HHATL depletion.
• SHH inhibition or DRP1 overexpression ameliorated HHATL-depletion-induced cardiac hypertrophy and mitochondrial dysfunction.

Conclusions:

• HHATL depletion activates the SHH/DRP1 axis, leading to cardiac hypertrophy.
• Reduced HHATL promotes hypertrophic markers, ROS generation, and mitochondrial dysfunction.
• This study provides strong evidence for HHATL's role in cardiac hypertrophy and its potential as a therapeutic target.