P2Y13 receptor regulates HDL metabolism and atherosclerosis in vivo.
High-density lipoprotein (HDL) is known to protect against atherosclerosis by promoting the reverse cholesterol transport. A new pathway for the regulation of HDL-cholesterol (HDL-c) removal involving F1-ATPase and P2Y13 receptor (P2Y13R) was described in vitro, and recently in mice. However, the physiological role of F1-ATPase/P2Y13R pathway in the modulation of vascular pathology i.e. in the development of atherosclerotic plaques is still unknown. We designed a specific novel agonist (CT1007900) of the P2Y13R that caused stimulation of bile acid secretion associated with an increased uptake of HDL-c in the liver after single dosing in mice. Repeated dose administration in mice, for 2 weeks, stimulated the apoA-I synthesis and formation of small HDL particles. Plasma samples from the agonist-treated mice had high efflux capacity for mobilization of cholesterol in vitro compared to placebo group. In apoE-/- mice this agonist induced a decrease of atherosclerotic plaques in aortas and carotids. The specificity of P2Y13R pathway in those mice was assessed using adenovirus encoding P2Y13R-shRNA. These results demonstrate that P2Y13R plays a pivotal role in the HDL metabolism and could also be a useful therapeutic agent to decrease atherosclerosis. In this study, the up-regulation of HDL-c metabolism via activation of the P2Y13R using agonists could promote reverse cholesterol transport and promote inhibition of atherosclerosis progression in mice.
Cerenis Therapeutics SA, Labege, France.
Marine
M
Goffinet
Cerenis Therapeutics SA, Labege, France.
Claudine
C
Tardy
Cerenis Therapeutics SA, Labege, France.
Nadia
N
Boubekeur
Cerenis Therapeutics SA, Labege, France.
Guy
G
Cholez
Cerenis Therapeutics SA, Labege, France.
Alice
A
Bluteau
Cerenis Therapeutics SA, Labege, France.
Daniela C
DC
Oniciu
Cerenis Therapeutics Inc., Ann Arbor, Michigan, United States of America.
Narendra D
ND
Lalwani
Cerenis Therapeutics SA, Labege, France.
Jean-Louis H
JL
Dasseux
Cerenis Therapeutics SA, Labege, France.
Ronald
R
Barbaras
Cerenis Therapeutics SA, Labege, France.
Rudi
R
Baron
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism*; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008076:Cholesterol, HDL / Q000097:blood* / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D056945:Hep G2 Cells; D006801:Humans; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology*; D058226:Plaque, Atherosclerotic / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D058910:Purinergic P2 Receptor Agonists / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D018048:Receptors, Purinergic P2 / Q000502:physiology*
C000594593:6-(1-(2-dimethylaminopyrimidin-5-ylmethyl)piperidin-4-yl)-2-morpholin-4-yl-pyrimidin-4-ol; D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D009025:Morpholines; C486689:P2ry13 protein, mouse; D058910:Purinergic P2 Receptor Agonists; D011743:Pyrimidines; D018048:Receptors, Purinergic P2