PCSK9 deficiency reduces atherosclerosis, apolipoprotein B secretion, and endothelial dysfunction

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Autophagy Research

Background:

• Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds apoB, preventing its degradation and influencing VLDL/LDL production and atherogenesis.
• PCSK9's role in modulating autophagy and its impact on atherosclerosis require further molecular investigation.

Purpose of the Study:

• To investigate the molecular mechanisms by which PCSK9 influences autophagy and atherogenesis.
• To assess the impact of PCSK9 deletion on atherosclerosis development in a mouse model.

Main Methods:

• Generated atherosclerosis-prone mice lacking PCSK9 (LTp mice) by backcrossing Pcsk9-/- mice with Ldlr-/-Apobec1-/- (LDb) mice.
• Analyzed hepatic apoB secretion, autophagic flux, plasma lipid levels, LDL particle characteristics, and endothelial gene expression in LTp and LDb mice.
• Quantified atherosclerosis development in LTp and LDb mice.

Main Results:

• PCSK9 deletion in LDb mice decreased hepatic apoB secretion, increased autophagic flux, and reduced plasma IDL and LDL levels.
• LTp-LDLs were less atherogenic, with reduced cholesteryl ester and phospholipids, and induced lower endothelial expression of inflammatory and autophagy-related genes.
• LTp mice exhibited significantly reduced atherosclerosis (>4-fold) compared to LDb mice.

Conclusions:

• Absence of PCSK9 in LDb mice leads to decreased lipid/apoB levels, less atherogenic LDLs, and markedly reduced atherosclerosis.
• Modified LDLs in PCSK9-deficient mice may mediate reduced atherogenesis via effects on endothelial receptors and inflammatory/autophagy pathways.
• PCSK9 inhibition may provide clinical benefits through mechanisms independent of increased LDL receptor activity.