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Macrophage P2Y6 receptor signalling as a key mediator and therapeutic target in atherosclerosis
1Division of Cardiology, Department of Medicine Solna, Karolinska Institutet, Solna, Stockholm, 17177, Sweden.
Insights
Researchers found that blocking the P2Y6 receptor in macrophages can prevent foam cell formation and reduce atherosclerosis plaque. Thiamine pyrophosphate (TPP) effectively inhibits this receptor, offering a potential new treatment for cardiovascular disease.
Area of Science:
- Cardiovascular Biology
- Immunology
- Pharmacology
Background:
- Atherosclerosis is a major cause of death, characterized by inflammation and lipid buildup.
- Purinergic signaling, specifically the P2Y6 receptor in macrophages, is implicated in atherosclerosis development.
- Understanding the molecular mechanisms of P2Y6 receptor involvement is crucial for therapeutic strategies.
Purpose of the Study:
- To elucidate the mechanistic role of macrophage P2Y6 receptors in foam cell formation and atherosclerotic plaque progression.
- To identify potential therapeutic agents targeting the P2Y6 receptor pathway.
Main Methods:
- Utilized RNA sequencing, proteomics, and functional assays in cellular and animal models.
- Validated findings using human atherosclerotic tissues.
- Investigated the phospholipase Cβ (PLCβ)/store-operated Ca2+ entry/calreticulin/scavenger receptor A (SR-A) pathway.
Main Results:
- Macrophage P2Y6 receptors drive foam cell formation and plaque development via the PLCβ/Ca2+ entry/calreticulin/SR-A pathway.
- Thiamine pyrophosphate (TPP) was identified as a potent P2Y6 receptor antagonist.
- TPP significantly inhibited foam cell formation and reduced atherosclerotic plaque burden in mice without toxicity.
Conclusions:
- P2Y6 receptors are key mediators in atherosclerosis pathogenesis.
- TPP demonstrates therapeutic potential as a P2Y6 receptor antagonist for treating atherosclerosis.
- Targeting macrophage P2Y6 receptors offers a promising strategy for cardiovascular disease intervention.
Abstract:
Atherosclerosis, a chronic inflammatory disease driven by lipid deposition and immune cell activation, remains a leading cause of cardiovascular morbidity and mortality. Emerging evidence highlights the role of purinergic signalling in atherogenesis, particularly the P2Y6 receptor in macrophages [1]. Using RNA sequencing, proteomics, expression and functional validation in cells, mouse models and human materials, this study provides comprehensive mechanistic insights into how macrophage P2Y6 receptors contribute to foam cell formation and plaque development through the phospholipase Cβ (PLCβ)/store-operated Ca2+ entry/calreticulin/scavenger receptor A (SR-A) pathway. Furthermore, the study identifies thiamine pyrophosphate (TPP) as a potent P2Y6 receptor antagonist, effectively inhibiting foam cell formation and reducing plaque burden in atherosclerotic mice, without inducing toxicity. These findings establish P2Y6 receptors as promising therapeutic targets in atherosclerosis and introduce TPP as a potential clinical candidate for intervention.
