EDITORIAL

Cardiovascular Research (2014) 102, 339–341 doi:10.1093/cvr/cvu108

Purinergic receptors and atherosclerosis: emerging role for vessel wall P2Y12 Bernhard H. Rauch 1* and Ja´nos G. Filep 2* 1 Centre of Drug Absorption and Transport, Institute of Pharmacology, University Medicine Greifswald, Greifswald 17487, Germany; and 2Department of Pathology and Cell Biology, University of Montreal, and Research Center, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada H1T 2M4

Online publish-ahead-of-print 22 April 2014

This editorial refers to ‘Vessel wall, not platelet, P2Y12 potentiates early atherogenesis’ by L.E. West et al., pp. 429 –435, this issue.

The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.

* Corresponding author. Tel: +49 3834865650 (B.H.R.)/+1 5142523400 (J.G.F.); fax: +49 3834865631 (B.H.R.)/+1 5142523569 (J.G.F.). Email: [email protected] (B.H.R.)/ [email protected] (J.G.F.) Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected]

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Platelets play a key role in primary haemostasis and also represent an important interface between thrombosis, immunity, and atherogenesis.1 Platelet-triggered inflammatory pathways contribute to the formation of atherosclerotic lesions and atherothrombosis. Platelets express receptors for a variety of agonists that initiate platelet activation, which is then amplified and sustained by activation of the G-protein-coupled purinergic receptor P2Y12. P2Y12 mediates platelet aggregation and secretion of platelet granule contents in response to ADP.2 P2Y12 is also a wellestablished target for anti-thrombotic drugs, such as the thienopyridine compounds ticlopidine, clopidogrel, and prasugrel or the direct, reversible antagonists ticagrelor, cangrelor, and elinogrel.2 Clinical studies have shown that in addition to preventing arterial thrombus formation in patients with coronary artery syndromes or after stent implantation, anti-thrombotic/anti-platelet therapy is also associated with systemic anti-inflammatory effects.3 While these findings imply an important role for P2Y12 in the regulation of platelet functions, P2Y12 expression is not restricted to platelets. Indeed, accumulating data indicate that P2Y12 may directly mediate pro-inflammatory and atherogenic actions in the vessel wall apparently independently of platelet activation. West et al. 4 provide evidence supporting this notion by describing a role for vessel wall, but not platelet, P2Y12 in the development of early atherosclerotic lesions. West et al. utilized the well-established ApoE-deficient mice model of atherosclerosis and generated ApoE2/2 P2Y2/2 (DK) mice by back12 crossing P2Y12-deficient mice into ApoE2/2 mice. Using homologous and heterogous bone marrow transplantation, the authors have generated chimeric mice to distinguish the contribution of platelet P2Y12 from vessel wall P2Y12 to early atheroma formation evoked by high-fat Western diet for 4 weeks. The key observations of this study is that mice deficient of vessel wall P2Y12 (DK) develop smaller atherosclerotic lesions compared with vessel wall P2Y12-expressing animals (ApoE). This effect was not reversed in mice transplanted with ApoE-bone marrow. Moreover, mice transplanted with P2Y12-deficient bone

marrow did not exhibit significantly altered early lesion progression. The intriguing conclusion from these experiments is that vessel wall rather than platelet P2Y12 contributes to early lesion development in these animals. An earlier study from the same laboratory identified a predominant role for platelet P2Y12 in neointima formation in response to ferric chloride-induced arterial injury and thrombosis.5 These findings emphasize the critical role of platelets (and other blood-borne cells) in modulating the vessel wall response to injury. However, these observations do not exclude a role for P2Y12 in the vessel wall because P2Y12 expression would likely be higher in vessel wall cells of atherosclerotic than in naive animals. In human vascular smooth muscle cells, P2Y12 expression is transcriptionally regulated via NK-kB, a key regulator of pro-inflammatory signalling pathways.6 Activation of the NF-kB signalling pathway in atherosclerosis-prone areas has been well documented.7 Another recent study also evaluated the role of P2Y12 in lesion progression in ApoE mice following 20 weeks of high-fat diet.8 Consistent with the findings of West et al.,4 P2Y12 deficiency was also found to attenuate late lesion progression. However, under this condition, both platelet and vessel wall P2Y12 appeared to contribute to lesion progression. This would point to an increasing contribution of platelet P2Y12 to atherogenesis with a particularly pronounced role in the advanced lesion. This notion is in agreement with clinical observations of enhanced platelet reactivity in patients with advanced stages of athero-thrombotic diseases.9 Over the past years, it became evident that haematopoietic as well as non-haematopoietic cells, including cells present in the vessel wall, express P2Y12.2 Possible candidate cell types in the vessel wall, in which P2Y12 expression may have relevance to atherogenesis include endothelial cells, smooth muscle cells, and immune cells such as monocytes and macrophages. P2Y12 expression has been reported in endothelial cells, where its expression may be transcriptionally regulated by certain toxins, such as nicotine.10,11 Human vascular smooth muscle cells also express P2Y12.6,10,12 In these cells, ligation of P2Y12 has been implicated in the regulation of calcium signalling and vasoconstriction.2 In addition, thrombin, the central regulator of coagulation, has been shown to enhance P2Y12 transcription through activation of the NF-kB signalling pathway in human vascular smooth muscle cells in vitro.6 Possible actions of smooth muscle P2Y12 may include induction of pro-inflammatory cytokine production and Gai-mediated signalling.6

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An obvious limitation of the study of West et al. is that it provides no information on the cell types expressing P2Y12 in the vessel wall. The signalling pathways downstream of platelet P2Y12 have extensively been studied.13 Activation of P2Y12 inhibits adenylate cyclase activity and subsequently reduces cAMP-mediated signalling such as granule secretion and regulates PI3 kinase and Akt signalling.13 Whether ligation of P2Y12 triggers similar pathways in vessel wall cells, i.e. in smooth muscle or endothelial cells, remains speculative. Potential proinflammatory and atherogenic effects of P2Y12 may involve signalling pathways known to be present in both platelets and smooth muscle cells; for example, coupling to surface toll-like receptors or secretion of growth factors.14,15 Figure 1 summarizes the possible actions and transcriptional regulation of P2Y12 in cells of the vessel wall. An unexpected observation in this study was the failure of the P2Y12 inhibitors ticagrelor and clopidogrel to reduce lesion size at the early disease stage.4 Earlier studies have reported an effective inhibition of ADP-induced vasoconstriction by ticagrelor and clopidogrel in isolated arteries.12 Whether the unresponsiveness to these anti-platelet compounds was due to their limited bioavailability within the vessel wall and/or differences in platelet and vessel wall P2Y12 sensitivity to inhibitors remains to be investigated. However, indirect evidence suggests systemic anti-inflammatory effects of P2Y12 inhibitors, which may extend beyond inhibition of platelet functions.3 Clearly, additional studies are needed to address the impact of P2Y12 antagonists on the progression of atherosclerotic lesions and possibly plaque rupture. One perspective for the clinical use of P2Y12 inhibitors is to define the role of vessel wall P2Y12 for vascular lesion progression. The study of West et al. 4 provides a solid starting point for such future studies. Considering the

complexity of platelet and vessel wall P2Y12-mediated actions, it remains a future challenge to investigate whether therapeutic interventions aimed to targeting vessel wall P2Y12 could have clinical benefits for patients with atherosclerosis.

Conflict of interest: none declared.

Funding This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB612, TPB11 to B.H.R.) and the Canadian Institutes of health research (MOP-97742 to J.G.F.).

References 1. von Hundelshausen P, Weber C. Platelets as immune cells. Bridging inflammation and cardiovascular disease. Circ Res 2007;100:27 –40. 2. Gachet C. P2Y(12) receptors in platelets and other hematopoietic and nonhematopoietic cells. Purinergic Signal 2012;8:609 –619. 3. Steinhubl SR, Badimon JJ, Bhatt DL, Herbert JM, Luscher TF. Clinical evidence for antiinflammatory effects of antiplatelet therapy in patients with atherothrombotic disease. Vasc Med 2007;12:113 –122. 4. West LE, Steiner T, Judge HM, Francis SE, Storey RF. Vessel wall, not platelet, P2Y12 potentiates early atherogenesis. Cardiovasc Res 2014;102:429–435. 5. Evans DJ, Jackman LE, Chamberlain J, Crosdale DJ, Judge HM, Jetha K, Norman KE, Francis SE, Storey RF. Platelet P2Y(12) receptor influences the vessel wall response to arterial injury and thrombosis. Circulation 2009;119:116–122. 6. Rauch BH, Rosenkranz AC, Ermler S, Bo¨hm A, Driessen J, Fischer JW, Sugidachi A, Jakubowski JA, Schro¨r K. Regulation of functionally active P2Y12 ADP receptors by thrombin in human smooth muscle cells and the presence of P2Y12 in carotid artery lesions. Arterioscler Thromb Vasc Biol 2010;30:2434 –2442. 7. Tabas I, Glass CK. Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 2013;339:166–172.

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Figure 1 Schematic representation of the potential role for vessel wall P2Y12 in atherosclerotic lesion progression. In addition to platelets, expression of P2Y12 has been reported in endothelial cells, smooth muscle cells, and immune cells. Thrombin, growth factors and nicotine may induce NF-kB-mediated transcription and subsequent expression of P2Y12 on the cell surface. The study of West et al. 4 indicates that activation of vessel wall rather than platelet P2Y12 contribute to the development of early atherosclerotic plaques. This may reflect a pro-inflammatory function of P2Y12 in the vessel wall. ADP-triggered pro-inflammatory signalling pathways coupled with NF-kB-regulated pathways would lead to chronic inflammation, cell proliferation, and ultimately progression of atherosclerotic lesions. Intriguingly, clinically approved P2Y12 antagonists, which effectively block platelet P2Y12 failed to affect atherosclerotic lesion progression in ApoE-deficient mice fed a Western diet for 4 weeks. ADP, adenosine-diphosphate; GPCRs, G-protein-coupled receptors; Gi, Gq, G-proteins coupling to GPCRs; TLRs, toll-like receptors.

Editorial

8. Li D, Wang Y, Zhang L, Luo X, Li J, Chen X, Niu H, Wank K, Sun Y, Wang X, Yan Y, Chai W, Gartner TK, Liu J. Roles of purinergic receptor P2Y, G protein-coupled 12 in the development of atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2012;32:e81 –e89. 9. Ferreiro JL, Angiolillo DJ. Challenges and perspectives of antiplatelet therapy in patients with diabetes mellitus and coronary artery disease. Curr Pharm Des 2012; 18:5273 – 5293. 10. Shanker G, Kontos JL, Eckman DM, Wesley-Farrington D, Sane DC. Nicotine upregulates the expression of P2Y12 on vascular cells and megakaryoblasts. J Thromb Thrombolysis 2006;22:213 –220. 11. Lee CW, Hwang I, Park CS, Lee H, Park DW, Kang SJ, Lee SW, Kim YH, Park SW, Park SJ. Comparison of differential expression of P2Y12 receptor in culprit coronary plaques in patients with acute myocardial infarction versus stable angina pectoris. Am J Cardiol 2011; 108:799 – 803.

341 12. Wihlborg AK, Wang L, Braun OO, Eyjolfsson A, Gustafsson R, Gudbjartsson T, Erlinge D. ADP receptor P2Y12 is expressed in vascular smooth muscle cells and stimulates contraction in human blood vessels. Arterioscler Thromb Vasc Biol 2004;24: 1810– 1815. 13. Li Z, Delaney MK, O’Brien KA, Du X. Signaling during platelet adhesion and activation. Arterioscler Thromb Vasc Biol 2010;30:2341 –2349. 14. Kalvegren H, Skoglund C, Helldahl C, Lerm M, Grenegard M, Bengtsson T. Toll-like receptor 2 stimulation of platelets is mediated by purinergic P2X1-dependent Ca2+ mobilisation, cyclooxygenase and purinergic P2Y1 and P2Y12 receptor activation. Thromb Haemost 2010;103:398 –407. 15. Blair P, Rex S, Vitseva O, Beaulieu L, Tanriverdi K, Chakrabarti S, Havashi C, Genco CA, Iafrati M, Freedman JE. Stimulation of Toll-like receptor 2 in human platelets induces a thromboinflammatory response through activation of phosphoinositide 3-kinase. Circ Res 2009;104:346 –354.

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Purinergic receptors and atherosclerosis: emerging role for vessel wall P2Y12.

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