Cardiomyocyte-specific PCSK9 deficiency compromises mitochondrial bioenergetics and heart function

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Metabolic Regulation

Background:

• Pro-protein convertase subtilisin-kexin type 9 (PCSK9) primarily regulates systemic cholesterol, with its cardiac role less understood due to links with lipid metabolism.
• Investigating PCSK9's specific function in the heart is crucial for understanding cardiac health and disease.

Purpose of the Study:

• To elucidate the specific function of PCSK9 within cardiomyocytes.
• To analyze the impact of cardiomyocyte-specific PCSK9 deficiency on cardiac function and metabolism.

Main Methods:

• Generated and analyzed mice with cardiomyocyte-specific Pcsk9 deficiency (CM-Pcsk9-/-).
• Performed acute Pcsk9 silencing in adult cardiomyocyte-like cells.
• Utilized transcriptomic analysis, Seahorse flux analysis, and mitochondrial assays.

Main Results:

• CM-Pcsk9-/- mice exhibited reduced contractile capacity, impaired cardiac function, and premature death.
• Hearts from CM-Pcsk9-/- mice showed altered energy metabolism, reduced mitochondrial function, and impaired electron transport chain (ETC) complexes.
• Acute Pcsk9 silencing in cardiomyocytes reduced ETC activity and impaired mitochondrial metabolism.

Conclusions:

• PCSK9, even at low cardiac expression, is vital for cardiomyocyte metabolic function.
• PCSK9 deficiency in cardiomyocytes leads to cardiomyopathy, impaired heart function, and compromised energy production.
• These findings reveal a novel intrinsic role for PCSK9 in maintaining cardiac energy homeostasis.