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Updated: Dec 7, 2025
Ferric Chloride-induced Murine Thrombosis Models
Published on: September 5, 2016
PCSK9 (Proprotein Convertase Subtilisin/Kexin 9) Enhances Platelet Activation, Thrombosis, and Myocardial Infarct
Zhiyong Qi1, Liang Hu2, Jianjun Zhang3
1Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China (Z.Q., W.Y., D.J., Z.Y., K.Y., A.S., J.Q., J.G.).
Insights
Proprotein convertase subtilisin/kexin 9 (PCSK9) directly promotes platelet activation and thrombosis by binding to CD36. Aspirin and PCSK9 inhibitors can prevent these thrombotic complications, suggesting combined therapy for high-risk patients.
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.
Background:
PCSK9 (proprotein convertase subtilisin/kexin 9), mainly secreted by the liver and released into the blood, elevates plasma low-density lipoprotein cholesterol by degrading low-density lipoprotein receptor. Pleiotropic effects of PCSK9 beyond lipid metabolism have been shown. However, the direct effects of PCSK9 on platelet activation and thrombosis, and the underlying mechanisms, as well, still remain unclear.
Methods:
We detected the direct effects of PCSK9 on agonist-induced platelet aggregation, dense granule ATP release, integrin αIIbβ3 activation, α-granule release, spreading, and clot retraction. These studies were complemented by in vivo analysis of FeCl3-injured mouse mesenteric arteriole thrombosis. We also investigated the underlying mechanisms. Using the myocardial infarction (MI) model, we explored the effects of PCSK9 on microvascular obstruction and infarct expansion post-MI.
Results:
PCSK9 directly enhances agonist-induced platelet aggregation, dense granule ATP release, integrin αIIbβ3 activation, P-selectin release from α-granules, spreading, and clot retraction. In line, PCSK9 enhances in vivo thrombosis in a FeCl3-injured mesenteric arteriole thrombosis mouse model, whereas PCSK9 inhibitor evolocumab ameliorates its enhancing effects. Mechanism studies revealed that PCSK9 binds to platelet CD36 and thus activates Src kinase and MAPK (mitogen-activated protein kinase)-extracellular signal-regulated kinase 5 and c-Jun N-terminal kinase, increases the generation of reactive oxygen species, and activates the p38MAPK/cytosolic phospholipase A2/cyclooxygenase-1/thromboxane A2 signaling pathways downstream of CD36 to enhance platelet activation, as well. Using CD36 knockout mice, we showed that the enhancing effects of PCSK9 on platelet activation are CD36 dependent. It is important to note that aspirin consistently abolishes the enhancing effects of PCSK9 on platelet activation and in vivo thrombosis. Last, we showed that PCSK9 activating platelet CD36 aggravates microvascular obstruction and promotes MI expansion post-MI.
Conclusions:
PCSK9 in plasma directly enhances platelet activation and in vivo thrombosis, and MI expansion post-MI, as well, by binding to platelet CD36 and thus activating the downstream signaling pathways. PCSK9 inhibitors or aspirin abolish the enhancing effects of PCSK9, supporting the use of aspirin in patients with high plasma PCSK9 levels in addition to PCSK9 inhibitors to prevent thrombotic complications.
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