Increased atherosclerosis in P2Y13/apolipoprotein E double-knockout mice: contribution of P2Y13 to reverse cholesterol transport.

Laeticia Lichtenstein, Nizar Serhan, Sara Espinosa-Delgado, Aurélie Fabre, Wijtske Annema, Uwe J F Tietge, Bernard Robaye, Jean-Marie Boeynaems, Muriel Laffargue, Bertrand Perret, Laurent O Martinez

Cardiovascular research 2015 May 1

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High-density lipoproteins (HDLs) protect against atherosclerosis mainly due to their function in hepatobiliary reverse cholesterol transport (RCT). This is a process whereby excess cholesterol from peripheral tissues is transported by HDL particles to the liver for further metabolism and biliary excretion. Hepatic uptake of HDL holoparticles involves the P2Y13 receptor, independently of the selective cholesteryl ester uptake mediated by scavenger receptor class B, type I (SR-BI). Accordingly, P2Y13-deficient mice (P2Y13 (-/-)) have impaired RCT. This study assessed whether P2Y13 deficiency would affect atherosclerotic development. P2Y13 (-/-) mice were crossbred with atherosclerosis-prone apoE(-/-) mice. When 15 weeks old, P2Y13 (-/-)/apoE(-/-) mice had more aortic sinus lesions than apoE(-/-) mice. Bone marrow transplantation showed that the absence of the P2Y13 receptor in blood cells did not lead to significantly greater atherosclerotic plaque size formation compared with control apoE(-/-) reconstituted animals. Conversely, the absence of the P2Y13 receptor, except in blood cells, resulted in lesion sizes similar to that in P2Y13 (-/-)/apoE(-/-) reconstituted mice, pointing to a role for non-haematopoietic-derived P2Y13. Unexpectedly, P2Y13 (-/-)/apoE(-/-) mice displayed a lower HDL-cholesterol level than apoE(-/-) mice, which might be due to greater SR-BI expression in the liver. However, P2Y13 deficiency in apoE(-/-) mice was translated into reduced biliary and faecal sterol excretion and impaired RCT from macrophage to faeces, suggesting that an alteration in hepatobiliary RCT could be solely responsible for the greater atherosclerosis observed. The P2Y13 receptor protects against atherosclerosis, primarily through its role in hepatobiliary RCT. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Citation

Laeticia Lichtenstein, Nizar Serhan, Sara Espinosa-Delgado, Aurélie Fabre, Wijtske Annema, Uwe J F Tietge, Bernard Robaye, Jean-Marie Boeynaems, Muriel Laffargue, Bertrand Perret, Laurent O Martinez. Increased atherosclerosis in P2Y13/apolipoprotein E double-knockout mice: contribution of P2Y13 to reverse cholesterol transport. Cardiovascular research. 2015 May 1;106(2):314-23