Roles of purinergic receptor P2Y, G protein-coupled 12 in the development of atherosclerosis in apolipoprotein E-deficient mice.

Abstract

OBJECTIVE:

The aim of the study was to evaluate the role of purinergic receptor P2Y, G protein-coupled 12 (P2Y12), an ADP receptor, in the development of atherosclerotic lesions.

METHODS AND RESULTS:

Apolipoprotein E-null mice were crossed with P2y12(-/-) mice to generate double knockout mice. The double knockout mice and the control apolipoprotein E-null mice were fed a high-fat diet for 20 weeks. Assessment of the atherosclerotic lesions in the control and double knockout mice demonstrated that P2Y12 deficiency caused a diminished lesion area, an increased fibrous content at the plaque site, and decreased monocyte/macrophage infiltration of the lesions. Polymerase chain reaction studies revealed that white blood cells do not express significant levels of P2Y12. Bone marrow transplantation experiments confirmed that P2Y12 expressed on platelets is a key factor responsible for atherosclerosis, but do not exclude a role of smooth muscle cell P2Y12. Supernatant fluid from activated P2y12(+/+) but not P2y12(-/-) platelets was capable of causing monocyte migration. In vitro studies showed that platelet P2Y12 deficiency suppressed platelet factor 4 secretion and P-selectin expression. Further work demonstrated that platelet P2Y12, through inhibition of the cAMP/protein kinase A pathway, critically regulates the release of platelet factor 4, and thereby affects monocyte recruitment and infiltration.

CONCLUSIONS:

These results demonstrate that P2Y12 modulates atherogenesis, at least in part by augmenting inflammatory cell recruitment via regulation of platelet α-granule release.

• Authors: Ding Li, Yanhua Wang, Lin Zhang, Xinping Luo, Jian Li, Xuejin Chen, Haixia Niu, Kemin Wang, Yueping Sun, Xuefeng Wang, Yan Yan, Weiran Chai, T Kent Gartner, Junling Liu
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 32 Issue 8 Pg. e81-9 (Aug 2012) ISSN: 1524-4636 [Electronic] United States
• PMID: 22628428 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins E
• Cytokines
• P2ry12 protein, mouse
• Receptors, Purinergic P2Y12
• Cyclic AMP-Dependent Protein Kinases

Topics

• Animals
• Apolipoproteins E (deficiency, metabolism)
• Atherosclerosis (drug therapy, etiology)
• Blood Platelets (chemistry)
• Bone Marrow Transplantation
• Cyclic AMP-Dependent Protein Kinases (antagonists & inhibitors)
• Cytokines (blood)
• Cytoplasmic Granules (metabolism)
• Female
• Leukocytes (physiology)
• Macrophages (physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Platelet Activation
• Receptors, Purinergic P2Y12 (analysis, physiology)
• Signal Transduction
• Tunica Intima (pathology)