Macrophage P2Y6 receptor deficiency or antagonism with thiamine pyrophosphate alleviated atherogenesis by decreasing plaque formation and lipid deposition.
Does P2Y6R deletion or antagonism prevent atherogenesis in mouse models?
Macrophage P2Y6R deletion or antagonism with thiamine pyrophosphate attenuates atherosclerosis by limiting foam cell formation, suggesting a potential therapeutic target.
BACKGROUND AND AIMS: Macrophage-derived foam cells play a causal role during the pathogenesis of atherosclerosis. P2Y6 receptor (P2Y6R) highly expressed has been considered as a disease-causing factor in atherogenesis, but the detailed mechanism remains unknown. This study aims to explore P2Y6R in regulation of macrophage foaming, atherogenesis, and its downstream pathways. Furthermore, the present study sought to find a potent P2Y6R antagonist and investigate the feasibility of P2Y6R-targeting therapy for atherosclerosis. METHODS: The P2Y6R expression was examined in human atherosclerotic plaques and mouse artery. Atherosclerosis animal models were established in whole-body P2Y6R or macrophage-specific P2Y6R knockout mice to evaluate the role of P2Y6R. RNA sequencing, DNA pull-down experiments, and proteomic approaches were performed to investigate the downstream mechanisms. High-throughput Glide docking pipeline from repurposing drug library was performed to find potent P2Y6R antagonists. RESULTS: The P2Y6R deficiency alleviated atherogenesis characterized by decreasing plaque formation and lipid deposition of the aorta. Mechanically, deletion of macrophage P2Y6R significantly inhibited uptake of oxidized low-density lipoprotein through decreasing scavenger receptor A expression mediated by phospholipase Cβ/store-operated calcium entry pathways. More importantly, P2Y6R deficiency reduced the binding of scavenger receptor A to CALR, accompanied by dissociation of calreticulin and STIM1. Interestingly, thiamine pyrophosphate was found as a potent P2Y6R antagonist with excellent P2Y6R antagonistic activity and binding affinity, of which the pharmacodynamic effect and mechanism on atherosclerosis were verified. CONCLUSIONS: Macrophage P2Y6R regulates phospholipase Cβ/store-operated calcium entry/calreticulin signalling pathway to increase scavenger receptor A protein level, thereby improving foam cell formation and atherosclerosis, indicating that the P2Y6R may be a potential therapeutic target for intervention of atherosclerotic diseases using P2Y6R antagonists including thiamine pyrophosphate.
“A recent study published in the European Heart Journal identified macrophages as the predominant site of P2Y6 receptor activation. The authors analyzed data from a public database and found that P2Y6 receptor mRNA levels were elevated in human atherosclerotic plaques, with the most abundant expression in macrophages from human atherosclerotic arteries. The upregulation of P2Y6 protein levels in macrophages was further observed in both the aortic roots of high-fat diet (HFD)-fed LDLR−/− mice and human carotid atherosclerotic plaques.”
Li et al. (Thu,) conducted a other in Atherosclerosis. P2Y6R deficiency or antagonism (thiamine pyrophosphate) was evaluated on Atherogenesis (plaque formation and lipid deposition). Macrophage P2Y6 receptor deficiency or antagonism with thiamine pyrophosphate alleviated atherogenesis by decreasing plaque formation and lipid deposition.