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P2Y6 receptor potentiates pro-inflammatory responses in macrophages and exhibits differential roles in atherosclerotic lesion development.

Garcia RA, Yan M, Search D, Zhang R, Carson NL, Ryan CS, Smith-Monroy C, Zheng J, Chen J, Kong Y, Tang H, Hellings SE, Wardwell-Swanson J, Dinchuk JE, Psaltis GC, Gordon DA, Glunz PW, Gargalovic PS - PLoS ONE (2014)

Bottom Line: P2Y(6)-mediated inflammatory responses were also observed, albeit to a lesser extent, in macrophages endogenously expressing P2Y(6) and in acute peritonitis models of inflammation.P2Y(6) receptor augments pro-inflammatory responses in macrophages and exhibits a pro-atherogenic role in hematopoietic cells.However, the overall impact of whole body P2Y(6) deficiency on atherosclerosis appears to be modest and could reflect additional roles of P2Y(6) in vascular disease pathophysiologies, such as aneurysm formation.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Drug Discovery, Bristol-Myers Squibb Company, Pennington, New Jersey, United States of America.

ABSTRACT

Background: P2Y(6), 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 P2Y(6) deficiency on atherosclerosis.

Methodology/principal findings: Cell-based studies in 1321N1 astrocytoma cells, which lack functional P2Y(6) receptors, showed that exogenous expression of P2Y(6) induces a robust, receptor- and agonist-dependent secretion of inflammatory mediators IL-8, IL-6, MCP-1 and GRO1. P2Y(6)-mediated inflammatory responses were also observed, albeit to a lesser extent, in macrophages endogenously expressing P2Y(6) and in acute peritonitis models of inflammation. To evaluate the role of P2Y(6) in atherosclerotic lesion development, we used P2Y(6)-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 P2Y(6) receptors in bone marrow-derived cells. In contrast, no effect on lesion development was observed in fat-fed whole body P2Y(6)xLDLR double knockout mice. Interestingly, in a model of enhanced vascular inflammation using angiotensin II, P2Y(6) deficiency enhanced formation of aneurysms and exhibited a trend towards increased atherosclerosis in the aorta of LDLR knockout mice.

Conclusions: P2Y(6) receptor augments pro-inflammatory responses in macrophages and exhibits a pro-atherogenic role in hematopoietic cells. However, the overall impact of whole body P2Y(6) deficiency on atherosclerosis appears to be modest and could reflect additional roles of P2Y(6) in vascular disease pathophysiologies, such as aneurysm formation.

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Accelerated Atherosclerosis development with Angiotensin II infusion.Atherosclerosis development measured in the aorta with oil red O. A) Quantification of en face lesion area in the thoracic aorta (ascending aorta to the diaphragm). Regional atherosclerosis in B) aortic arch and C) descending thoracic aorta segments. Group sizes: n = 9 P2Y6 WT mice; n = 14 P2Y6 KO mice. The fold change in P2Y6 lesion area is given relative to P2Y6 wild type levels. Not significant, n.s.
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pone-0111385-g006: Accelerated Atherosclerosis development with Angiotensin II infusion.Atherosclerosis development measured in the aorta with oil red O. A) Quantification of en face lesion area in the thoracic aorta (ascending aorta to the diaphragm). Regional atherosclerosis in B) aortic arch and C) descending thoracic aorta segments. Group sizes: n = 9 P2Y6 WT mice; n = 14 P2Y6 KO mice. The fold change in P2Y6 lesion area is given relative to P2Y6 wild type levels. Not significant, n.s.

Mentions: Given these findings, we wanted to further assess the impact of P2Y6 on atherogenesis in the context of enhanced vascular inflammation and subjected P2Y6 KO or WT control mice (both on an LDLR KO background) to angiotensin II infusion in addition to dietary challenge. Studies in LDLR and apolipoprotein E KO (ApoE KO) mice have shown that chronic infusion of angiotensin II promotes accelerated atherosclerosis development, vascular inflammation and extensive abdominal aneurysm formation [22], [23]. After 4 weeks of treatment with angiotensin II and high-fat diet, en face plaque analysis of the whole thoracic aorta, aortic arch or descending thoracic aorta did not reveal significant differences between P2Y6 KO and P2Y6 WT mice (Figure 6A-C). A non-significant trend towards increased plaque development was noted in the descending thoracic aorta with P2Y6 deficiency (2.2 fold increased vs. control, p = 0.07; Figure 6C). Unlike the BMT and pro-atherogenic dietary experiments described above, a modest increase in plasma total cholesterol was observed with P2Y6 deficiency vs. control (21%, p<0.01; Figure S5).


P2Y6 receptor potentiates pro-inflammatory responses in macrophages and exhibits differential roles in atherosclerotic lesion development.

Garcia RA, Yan M, Search D, Zhang R, Carson NL, Ryan CS, Smith-Monroy C, Zheng J, Chen J, Kong Y, Tang H, Hellings SE, Wardwell-Swanson J, Dinchuk JE, Psaltis GC, Gordon DA, Glunz PW, Gargalovic PS - PLoS ONE (2014)

Accelerated Atherosclerosis development with Angiotensin II infusion.Atherosclerosis development measured in the aorta with oil red O. A) Quantification of en face lesion area in the thoracic aorta (ascending aorta to the diaphragm). Regional atherosclerosis in B) aortic arch and C) descending thoracic aorta segments. Group sizes: n = 9 P2Y6 WT mice; n = 14 P2Y6 KO mice. The fold change in P2Y6 lesion area is given relative to P2Y6 wild type levels. Not significant, n.s.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4216081&req=5

pone-0111385-g006: Accelerated Atherosclerosis development with Angiotensin II infusion.Atherosclerosis development measured in the aorta with oil red O. A) Quantification of en face lesion area in the thoracic aorta (ascending aorta to the diaphragm). Regional atherosclerosis in B) aortic arch and C) descending thoracic aorta segments. Group sizes: n = 9 P2Y6 WT mice; n = 14 P2Y6 KO mice. The fold change in P2Y6 lesion area is given relative to P2Y6 wild type levels. Not significant, n.s.
Mentions: Given these findings, we wanted to further assess the impact of P2Y6 on atherogenesis in the context of enhanced vascular inflammation and subjected P2Y6 KO or WT control mice (both on an LDLR KO background) to angiotensin II infusion in addition to dietary challenge. Studies in LDLR and apolipoprotein E KO (ApoE KO) mice have shown that chronic infusion of angiotensin II promotes accelerated atherosclerosis development, vascular inflammation and extensive abdominal aneurysm formation [22], [23]. After 4 weeks of treatment with angiotensin II and high-fat diet, en face plaque analysis of the whole thoracic aorta, aortic arch or descending thoracic aorta did not reveal significant differences between P2Y6 KO and P2Y6 WT mice (Figure 6A-C). A non-significant trend towards increased plaque development was noted in the descending thoracic aorta with P2Y6 deficiency (2.2 fold increased vs. control, p = 0.07; Figure 6C). Unlike the BMT and pro-atherogenic dietary experiments described above, a modest increase in plasma total cholesterol was observed with P2Y6 deficiency vs. control (21%, p<0.01; Figure S5).

Bottom Line: P2Y(6)-mediated inflammatory responses were also observed, albeit to a lesser extent, in macrophages endogenously expressing P2Y(6) and in acute peritonitis models of inflammation.P2Y(6) receptor augments pro-inflammatory responses in macrophages and exhibits a pro-atherogenic role in hematopoietic cells.However, the overall impact of whole body P2Y(6) deficiency on atherosclerosis appears to be modest and could reflect additional roles of P2Y(6) in vascular disease pathophysiologies, such as aneurysm formation.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Drug Discovery, Bristol-Myers Squibb Company, Pennington, New Jersey, United States of America.

ABSTRACT

Background: P2Y(6), 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 P2Y(6) deficiency on atherosclerosis.

Methodology/principal findings: Cell-based studies in 1321N1 astrocytoma cells, which lack functional P2Y(6) receptors, showed that exogenous expression of P2Y(6) induces a robust, receptor- and agonist-dependent secretion of inflammatory mediators IL-8, IL-6, MCP-1 and GRO1. P2Y(6)-mediated inflammatory responses were also observed, albeit to a lesser extent, in macrophages endogenously expressing P2Y(6) and in acute peritonitis models of inflammation. To evaluate the role of P2Y(6) in atherosclerotic lesion development, we used P2Y(6)-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 P2Y(6) receptors in bone marrow-derived cells. In contrast, no effect on lesion development was observed in fat-fed whole body P2Y(6)xLDLR double knockout mice. Interestingly, in a model of enhanced vascular inflammation using angiotensin II, P2Y(6) deficiency enhanced formation of aneurysms and exhibited a trend towards increased atherosclerosis in the aorta of LDLR knockout mice.

Conclusions: P2Y(6) receptor augments pro-inflammatory responses in macrophages and exhibits a pro-atherogenic role in hematopoietic cells. However, the overall impact of whole body P2Y(6) deficiency on atherosclerosis appears to be modest and could reflect additional roles of P2Y(6) in vascular disease pathophysiologies, such as aneurysm formation.

Show MeSH
Related in: MedlinePlus