Study of the involvement of purinergic receptors in the development of atherosclerotic plaques in the mouse.

摘要

Introduction. Cardiovascular diseases resulting from atherosclerosis are a leading cause of death and morbidity in developed countries. Atherosclerosis is a chronic inflammatory disease of medium-sized arteries that leads to the formation of atherosclerotic plaques, which eventually may occlude the lumen. The present work investigated the role of P2Y receptors during atherosclerosis in apolipoprotein E-deficient (apoE-/-) mice, a well documented animal model to study the pathogenesis of atherosclerosis. P2Y receptors belong to the class of purinergic receptors, are activated by nucleotides (like ATP, ADP, UTP or UDP) and mediate a wide range of biological responses.; Results. We initially characterised P2Y1, P2Y2 and P2Y6(like) receptors on endothelial cells (ECs) and smooth muscle cells (SMCs) in the aorta of C57B16 mice and illustrated their role in the local regulation of the vascular tone. Next, we demonstrated that these nucleotide-evoked relaxations were impaired in plaque-containing aorta segments from apoE-/- mice. Moreover, we even noticed P2Y6-mediated constrictor responses in those atherosclerotic segments, which could lead to vascular spasm. However, we demonstrated full restoration of the EC-dysfunction upon gene transfer of paraoxonase-1 (PON1), thereby illustrating the beneficial effects of anti-oxidative enzymes like PON1 on the NO-bioavailability and subsequent vasodilator capacity.; Furthermore, we reported increased mRNA expression of P2Y6 receptors, but not of P2Y2 receptors in atherosclerotic regions. This increase was most likely due to recruitment of macrophages to the lesions. Moreover, the P2Y6 agonist UDP activated macrophages in vitro (iNOS induction and IL-6 release) pointing to a pro-inflammatory role of P2Y 6 receptors on macrophages.; Finally, in a pharmacological intervention study we showed that the non-selective purinergic receptor antagonists suramin and PPADS retarded plaque progression in apoE-/- mice, supporting the hypothesis that purinergic receptors promote atherogenesis.; Conclusion. We illustrated the role of P2Y receptors in the local regulation of the vascular tone. Moreover, the vasodilator effect of nucleotides was disturbed during atherosclerosis. We also documented a pro-inflammatory role of P2Y6 receptors on macrophages and found an upregulation of P2Y6 receptors in atherosclerotic plaques, which could point to a pro-atherosclerotic role of certain P2Y subtypes. The exact impact of P2Y receptors on atherogenesis requires, however, additional study.