PCSK9 deficiency rewires heart metabolism and drives heart failure with preserved ejection fraction

Area of Science:

• Cardiovascular Biology
• Metabolic Research
• Molecular Medicine

Background:

• Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low-density lipoprotein receptor (LDLR) levels.
• PCSK9 deficiency leads to increased lipid and lipoprotein receptor expression, potentially affecting cellular lipid accumulation.
• The impact of PCSK9 on cardiac metabolism and function remains incompletely understood.

Purpose of the Study:

• To investigate the effects of PCSK9 deficiency on heart metabolism and function.
• To determine the role of LDLR in PCSK9-mediated cardiac effects.
• To explore the contribution of circulating versus locally produced PCSK9 to cardiac dysfunction.

Main Methods:

• Evaluation of exercise resistance, muscle strength, and cardiac characteristics in wild-type, PCSK9 knockout, liver-specific PCSK9 knockout, and PCSK9/LDLR double knockout mice.
• Assessment of heart mitochondrial activity, cardiac metabolism, and gene expression.
• Analysis of cardiac parameters in human carriers of a PCSK9 loss-of-function variant.

Main Results:

• PCSK9 knockout mice exhibited reduced exercise resistance and echocardiographic signs of heart failure with preserved ejection fraction (HFpEF).
• Reduced mitochondrial activity and altered cardiac metabolism, with increased LDLR and CD36 expression and lipid accumulation, were observed in PCSK9 knockout mice.
• The cardiac phenotype in PCSK9 knockout mice was independent of LDLR, and liver-specific PCSK9 knockout models suggested a role for locally produced PCSK9.
• Human carriers of a PCSK9 loss-of-function variant showed increased left ventricular mass.

Conclusions:

• PCSK9 deficiency adversely affects cardiac lipid metabolism in an LDLR-independent manner.
• PCSK9 deficiency contributes to the development of HFpEF.
• These findings suggest a direct role for PCSK9 in maintaining cardiac metabolic homeostasis and function.