PCSK9 Promotes Atherosclerotic Plaque Instability by Inducing VSMC Ferroptosis through the YAP1-NUPR1 Axis

Area of Science:

• Cardiovascular Biology
• Cellular Mechanisms of Disease
• Molecular Cardiology

Background:

• Atherosclerosis is a leading cause of cardiovascular mortality, driven by plaque instability.
• Vulnerable atherosclerotic plaques can rupture, leading to major adverse cardiovascular events (MACE).
• Proprotein convertase subtilisin/kexin type 9 (PCSK9) is primarily known for lipid regulation, but its role in plaque instability is under investigation.

Purpose of the Study:

• To investigate the noncanonical role of PCSK9 in vascular smooth muscle cells (VSMCs) and its impact on atherosclerotic plaque instability.
• To elucidate the molecular mechanisms by which PCSK9 influences VSMC fate and plaque vulnerability.

Main Methods:

• Investigated PCSK9's effect on VSMC ferroptosis.
• Examined the interaction between PCSK9, Yes-associated protein 1 (YAP1), and nuclear factor 1 (NF1).
• Utilized cellular models to assess plaque vulnerability.

Main Results:

• PCSK9 overactivity significantly promotes ferroptotic cell death in VSMCs.
• This ferroptosis exacerbates atherosclerotic plaque vulnerability.
• PCSK9 interacts with YAP1, leading to its lysosomal degradation and subsequent suppression of NF1 expression.

Conclusions:

• PCSK9 plays a novel role in promoting plaque instability by inducing VSMC ferroptosis.
• Targeting PCSK9 offers a potential therapeutic strategy for plaque stabilization.
• This approach could help mitigate the incidence of major adverse cardiovascular events (MACE).