Dysfunctional HDL Promotes Platelet Apoptosis and Thrombosis in Familial Hypercholesterolemia

Area of Science:

• Cardiovascular Biology
• Lipid Metabolism
• Thrombosis Research

Background:

• Familial hypercholesterolemia (FH) is associated with dysfunctional high-density lipoprotein (HDL) enriched in lipid peroxidation products.
• This dysfunctional HDL may contribute to increased thrombotic risk, but its precise impact on platelet function and thrombosis is not fully understood.
• The potential for targeting HDL oxidation to restore its protective functions remains an open question.

Purpose of the Study:

• To investigate the effects of HDL from familial hypercholesterolemia (FH) patients on platelet activation and apoptosis.
• To determine if targeting HDL oxidation can mitigate prothrombotic effects in FH.
• To explore the role of scavenger receptor class B type 1 (SR-B1) and cluster of differentiation 36 (CD36) in HDL-mediated platelet responses.

Main Methods:

• Platelet function analysis using flow cytometry, transmission electron microscopy (TEM), western blotting, and transcriptome analysis.
• Evaluation of HDL effects on oxidized low-density lipoprotein (oxLDL)-induced platelet activation and apoptosis.
• In vivo thrombosis studies in LDL-receptor-deficient (Ldlr-/-) mice treated with 2-hydroxybenzylamine (2-HOBA), a lipid peroxidation scavenger.

Main Results:

• Platelets from FH subjects exhibited heightened activity, increased apoptosis, and altered pro- and anti-apoptotic protein levels compared to healthy controls.
• HDL from healthy individuals inhibited oxLDL-induced platelet activation and apoptosis, while FH-HDL exacerbated these effects.
• Treatment with 2-HOBA improved thrombosis outcomes and blood flow in Ldlr-/- mice, and blocking CD36 prevented the pro-apoptotic effects of FH-HDL.

Conclusions:

• Dysfunctional HDL in FH promotes platelet activation and apoptosis, contributing to a prothrombotic state.
• Targeting HDL oxidation with agents like 2-HOBA can restore HDL's protective functions and mitigate thrombosis risk in FH.
• CD36 plays a significant role in mediating the pro-thrombotic effects of dysfunctional FH-HDL.