Abstract 343: Inactivation of the P2Y2 Receptor Gene Reduces Atherosclerosis
Rationale: Nucleotides acting via P2Y2 nucleotide receptors (P2Y2R) regulate both migration of vascular smooth muscle cells and endothelial recruitment of monocyte/macrophage in vivo.
Objective: We aimed to determine whether inactivation of the P2Y2R gene protects against neointima hyperplasia and atherosclerosis.
Method and results: We performed femoral artery cuff injury in wild-type and P2Y2R-/- mice and examined neointima formation 14 days after injury, the time corresponding to peak SMC accumulation in this model. Wild-type mice exhibited a 190% increase in cellular proliferation (P<0.001) in the arterial wall as assessed by BrdU incorporation, and a 150% increase in neointima formation (P=0.010) compared to wild-type mice. There was no significant difference in the medial area between wild type and P2Y2R-/- mice. To assess the contribution of P2Y2R to atherosclerosis, we first generated P2Y2R-/-/ApoE-/- mice by mating ApoE-/- mice with P2Y2R-/- mice. We then examined the development of atherosclerotic lesions 30 weeks after mice were fed with standard chow diet, the time corresponding to widespread atherosclerotic lesions in the ApoE-/- mouse model. P2Y2R-/-/ApoE-/- andApoE-/- exhibited no differencesin blood pressure, number of circulating leukocytes, differentialcounts, or total blood cholesterol. The surface covered by atheroscleroticlesions in the entire aorta was significantly reduced in P2Y2R-/-/ApoE-/- mice as compared to ApoE-/-. The total intimal lesion area in the aortic sinus was significantlyless in P2Y2R-/-/ApoE-/- mice than in ApoE-/- mice. Mac-3 staining revealed a significant reduction in the percentage of total plaque area occupiedby macrophages in P2Y2R-/-/ApoE-/- mice compared with ApoE-/- mice.
Conclusion:These findings suggest that unraveling the molecular mechanisms associated with P2Y2R may lead to potential drug targets for the treatment of coronary syndromes and percutaneous coronary interventions.
- © 2012 by American Heart Association, Inc.