PCSK9 (Proprotein Convertase Subtilisin/Kexin 9) Enhances Platelet Activation, Thrombosis, and Myocardial Infarct...

Area of Science:

• Cardiovascular Biology
• Hematology
• Molecular Medicine

Background:

• Proprotein convertase subtilisin/kexin 9 (PCSK9) primarily regulates plasma low-density lipoprotein cholesterol by degrading the low-density lipoprotein receptor.
• While PCSK9 has known pleiotropic effects beyond lipid metabolism, its direct impact on platelet activation and thrombosis remains largely uncharacterized.

Purpose of the Study:

• To investigate the direct effects of PCSK9 on platelet activation, aggregation, and thrombosis.
• To elucidate the underlying molecular mechanisms by which PCSK9 influences platelet function.
• To evaluate the role of PCSK9 in myocardial infarction (MI) expansion and microvascular obstruction.

Main Methods:

• Assessed PCSK9's effects on platelet aggregation, dense granule ATP release, integrin αIIbβ3 activation, α-granule release, spreading, and clot retraction in vitro.
• Utilized a FeCl₃-induced mouse mesenteric arteriole thrombosis model for in vivo thrombosis assessment.
• Investigated mechanistic pathways involving CD36, Src kinase, MAPK signaling, reactive oxygen species, and thromboxane A₂.
• Examined PCSK9's role in a myocardial infarction (MI) model to assess microvascular obstruction and infarct expansion.

Main Results:

• PCSK9 directly enhanced agonist-induced platelet aggregation, dense granule ATP release, integrin αIIbβ3 activation, P-selectin release, spreading, and clot retraction.
• PCSK9 significantly increased in vivo thrombosis in mice, an effect ameliorated by the PCSK9 inhibitor evolocumab.
• Mechanistic studies revealed PCSK9 binds to platelet CD36, activating downstream Src kinase, MAPK pathways, reactive oxygen species generation, and the p38MAPK/cPLA2/COX-1/TXA2 cascade, which are CD36-dependent.
• Aspirin effectively abolished PCSK9-mediated platelet activation and in vivo thrombosis.
• PCSK9 activation of platelet CD36 exacerbated microvascular obstruction and promoted infarct expansion post-MI.

Conclusions:

• Plasma PCSK9 directly enhances platelet activation, in vivo thrombosis, and post-MI expansion via CD36-mediated signaling.
• PCSK9 inhibitors and aspirin effectively mitigate these pro-thrombotic effects.
• Combined therapy with aspirin and PCSK9 inhibitors may be beneficial for preventing thrombotic complications in patients with elevated PCSK9 levels.