TRIM40 Drives Pathological Cardiac Hypertrophy and Heart Failure via Ubiquitination of PKN2

Area of Science:

• Cardiology
• Molecular Biology
• Biochemistry

Background:

• Pathological cardiac hypertrophy is a significant risk factor for heart failure (HF).
• Understanding the molecular mechanisms underlying cardiac hypertrophy is crucial for developing effective treatments.
• E3 ubiquitin ligases play critical roles in regulating cellular processes, including cardiac remodeling.

Purpose of the Study:

• To investigate the role of the E3 ubiquitin ligase Tripartite Motif-Containing 40 (TRIM40) in the development of pathological cardiac hypertrophy.
• To elucidate the molecular mechanism by which TRIM40 influences cardiac hypertrophy.

Main Methods:

• Utilized TRIM40 knockout, cardiac-specific knockdown, and overexpressing mouse models.
• Induced pathological cardiac hypertrophy using angiotensin II (Ang II) infusion and transverse aortic constriction (TAC).
• Investigated the interaction between TRIM40 and PKN2, including ubiquitination and phosphorylation events.

Main Results:

• TRIM40 expression was elevated in hypertrophic hearts.
• TRIM40 deficiency attenuated cardiac hypertrophy and dysfunction, while overexpression worsened pathological remodeling.
• TRIM40 binds and K63-linked ubiquitinates PKN2, enhancing its phosphorylation at Ser815 and activating downstream signaling pathways.
• Pharmacological inhibition of PKN2 ameliorated cardiac remodeling induced by TRIM40 overexpression.

Conclusions:

• TRIM40 promotes cardiac hypertrophy and dysfunction through the ubiquitination and activation of PKN2.
• TRIM40 represents a potential therapeutic target for mitigating cardiac hypertrophy and preventing heart failure.