Abstract
BackgroundP2Y6, a purinergic receptor for UDP, is enriched in atherosclerotic lesions and is implicated in pro-inflammatory responses of key vascular cell types and macrophages. Evidence for its involvement in atherogenesis, however, has been lacking. Here we use cell-based studies and three murine models of atherogenesis to evaluate the impact of P2Y6 deficiency on atherosclerosis.Methodology/Principal FindingsCell-based studies in 1321N1 astrocytoma cells, which lack functional P2Y6 receptors, showed that exogenous expression of P2Y6 induces a robust, receptor- and agonist-dependent secretion of inflammatory mediators IL-8, IL-6, MCP-1 and GRO1. P2Y6-mediated inflammatory responses were also observed, albeit to a lesser extent, in macrophages endogenously expressing P2Y6 and in acute peritonitis models of inflammation. To evaluate the role of P2Y6 in atherosclerotic lesion development, we used P2Y6-deficient mice in three mouse models of atherosclerosis. A 43% reduction in aortic arch plaque was observed in high fat-fed LDLR knockout mice lacking P2Y6 receptors in bone marrow-derived cells. In contrast, no effect on lesion development was observed in fat-fed whole body P2Y6xLDLR double knockout mice. Interestingly, in a model of enhanced vascular inflammation using angiotensin II, P2Y6 deficiency enhanced formation of aneurysms and exhibited a trend towards increased atherosclerosis in the aorta of LDLR knockout mice.ConclusionsP2Y6 receptor augments pro-inflammatory responses in macrophages and exhibits a pro-atherogenic role in hematopoietic cells. However, the overall impact of whole body P2Y6 deficiency on atherosclerosis appears to be modest and could reflect additional roles of P2Y6 in vascular disease pathophysiologies, such as aneurysm formation.
Highlights
Mechanisms mediating inflammatory responses to tissue injury associated with atherosclerotic lesion development are critical to disease progression and clinical outcome
We examined the effect of whole-body deficiency on lesion formation in a standard dietary low density lipoprotein receptor (LDLR) KO model and angiotensin II-infused pro-inflammatory model to reveal a potentially novel role for P2Y6 in aneurysm formation
The observed response was directly correlated with P2Y6 expression level across the stable clones and was lost in parental cells or cells treated with medium pre-incubated with a nucleotide-degrading enzyme apyrase (Figure S1)
Summary
Mechanisms mediating inflammatory responses to tissue injury associated with atherosclerotic lesion development are critical to disease progression and clinical outcome. Nucleotides represent key signaling molecules with diverse biological actions They can be released to the extracellular space under a variety of stress conditions, such as tissue damage, infection, mechanical stimulation and hypoxia, and are considered to be danger signals or part of damage-associated molecular patterns (DAMPs) [2]. Nucleotides contribute to the inflammatory response by interacting with purinergic receptors on the cellular surface, activating downstream signaling pathways. P2Y6 receptor expression in lesions was enhanced with plaque development and was enriched primarily in macrophage foam cells. P2Y6, a purinergic receptor for UDP, is enriched in atherosclerotic lesions and is implicated in proinflammatory responses of key vascular cell types and macrophages. We use cell-based studies and three murine models of atherogenesis to evaluate the impact of P2Y6 deficiency on atherosclerosis
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