Reduced Atherosclerotic Lesions in P2Y ₁ /Apolipoprotein E Double-Knockout Mice

Abstract

Background— The P2Y 1 receptor plays a key role in arterial thrombosis and is widely expressed in many cell types involved in atherosclerosis. The aim of this study was to evaluate its potential involvement in the development of atherosclerotic lesions. Methods and Results— Apolipoprotein E–deficient ( ApoE −/− ) and P2Y 1 −/− / ApoE −/− mice were maintained on regular chow for 17 or 30 weeks before analysis of atherosclerotic lesions. At 17 weeks, lesions in the aortic sinus and entire aorta were smaller in P2Y 1 −/− / ApoE −/− compared with those in ApoE −/− animals. At 30 weeks, the aortic sinus lesions in P2Y 1 −/− / ApoE −/− mice were still diminished in size and displayed reduced inflammation, reflected by decreased macrophage infiltration and diminished VCAM-1 immunostaining, compared with those in ApoE −/− mice. They also had a lower smooth muscle cell content. Unexpectedly, bone marrow transplantation showed that the absence of the P2Y 1 receptor in blood cells only led to no significant modification of the lesion compared with control ApoE −/− reconstituted animals. Conversely, the absence of the P2Y 1 receptor except in blood cells resulted in a reduction in lesion size similar to that in control P2Y 1 −/− / ApoE −/− reconstituted mice, pointing to a role of non–hematopoietic-derived P2Y 1 receptors, most likely the endothelial or smooth muscle cell P2Y 1 receptors. In addition, although this was not statistically significant, plasma cholesterol levels were consistently decreased in P2Y 1 −/− animals, suggesting that a modification of lipid metabolism could be responsible for the observed phenotype. Conclusion— The P2Y 1 receptor contributes to atherosclerosis, primarily through its role in non–hematopoietic-derived cells.

P2X receptors regulate adenosine diphosphate release from hepatic cells

“…Elevated circulating nucleotide levels and sustained purinergic signaling may consequently promote inflammatory diseases [7,8]. Consistent with this view, knockout of P2Y and ion channel purinergic receptors (P2X) in mice has been shown to significantly reduce inflammatory disease in the heart, liver, kidney, and other tissues [9][10][11][12][13][14].…”

Molecular Biology of Atherosclerosis

“…P2Y 1 deficiency modestly decreased atherosclerosis in ApoE-deficient mice. Interestingly, the effect was due entirely to vessel wall expression, rather than hematopoetic cells including platelets (741). P2Y 1 signaling upregulates eNOS in endothelial cells, but the intermediate pathways are not well understood (372,759).…”

P2 receptors and platelet function

“…It is worthy to note that inhibition of the P2Y 1 receptor results in only moderate prolongation of the bleeding time, which could be advantageous in terms of safety. Additional advantages of targeting the P2Y 1 receptor rely on its role in vascular inflammation [127] and in atherosclerosis [128] (see below). As a consequence, this receptor could represent an attractive and original target for drugs with multiple sites of action in atherothrombosis and beyond in other inflammatory diseases.…”

“…Using P2Y 1 −/− mice crossed with ApoE −/− mice, a role of the P2Y 1 receptor in the development of atherosclerosis was demonstrated [128]. Interestingly, bone marrow transplantation experiments showed that the platelet receptor is not involved in this process, suggesting a possible role of the P2Y 1 receptor expressed in endothelial cells [128].…”

“…Using P2Y 1 −/− mice crossed with ApoE −/− mice, a role of the P2Y 1 receptor in the development of atherosclerosis was demonstrated [128]. Interestingly, bone marrow transplantation experiments showed that the platelet receptor is not involved in this process, suggesting a possible role of the P2Y 1 receptor expressed in endothelial cells [128]. We recently reported that the P2Y 1 receptor contributes to the upregulation of adhesion molecule (P-selectin, VCAM-1 and ICAM-1) exposure in TNFα-stimulated ECs by a mechanism involving p38 MAP kinase signalling pathway, which in turn facilitates recruitment of monocytes and their transmigration.…”