title: Inhibition of lysophosphatidic acid receptors 1 and 3 attenuates atherosclerosis development in LDL-receptor deficient mice.
abstract: Lysophosphatidic acid (LPA) is a natural lysophospholipid present at high concentrations within lipid-rich atherosclerotic plaques. Upon local accumulation in the damaged vessels, LPA can act as a potent activator for various types of immune cells through its specific membrane receptors LPA1/3.LPA elicits chemotactic, pro-inflammatory and apoptotic effects that lead to atherosclerotic plaque progression. In this study we aimed to inhibit LPA signaling by means of LPA1/3antagonism using the small molecule Ki16425. We show that LPA1/3inhibition significantly impaired atherosclerosis progression. Treatment with Ki16425 also resulted in reduced CCL2 production and secretion, which led to less monocyte and neutrophil infiltration. Furthermore, we provide evidence that LPA1/3blockade enhanced the percentage of non-inflammatory, Ly6Clowmonocytes and CD4+CD25+FoxP3+T-regulatory cells. Finally, we demonstrate that LPA1/3antagonism mildly reduced plasma LDL cholesterol levels. Therefore, pharmacological inhibition of LPA1/3receptors may prove a promising approach to diminish atherosclerosis development.
authors.affiliation: Division of Biopharmaceutics, LACDR, Leiden University, The Netherlands.
authors.forename: Eva
authors.initials: E
authors.lastname: Kritikou
authors.affiliation: Division of Biopharmaceutics, LACDR, Leiden University, The Netherlands.
authors.forename: Gijs H M
authors.initials: GH
authors.lastname: van Puijvelde
authors.affiliation: Division of Biopharmaceutics, LACDR, Leiden University, The Netherlands.
authors.forename: Thomas
authors.initials: T
authors.lastname: van der Heijden
authors.affiliation: Division of Biopharmaceutics, LACDR, Leiden University, The Netherlands.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: van Santbrink
authors.affiliation: Division of Biopharmaceutics, LACDR, Leiden University, The Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: Swart
authors.affiliation: Division of Biopharmaceutics, LACDR, Leiden University, The Netherlands.
authors.forename: Frank H
authors.initials: FH
authors.lastname: Schaftenaar
authors.affiliation: Division of Biopharmaceutics, LACDR, Leiden University, The Netherlands.
authors.forename: Mara J
authors.initials: MJ
authors.lastname: Kröner
authors.affiliation: Division of Biopharmaceutics, LACDR, Leiden University, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Kuiper
authors.affiliation: Division of Biopharmaceutics, LACDR, Leiden University, The Netherlands.
authors.forename: Ilze
authors.initials: I
authors.lastname: Bot
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008078:Cholesterol, LDL / Q000097:blood; D004195:Disease Models, Animal; D004705:Endocytosis / Q000235:genetics; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage; D008246:Lysophospholipids / Q000235:genetics; D051379:Mice; D011422:Propionates / Q000008:administration & dosage; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; D008078:Cholesterol, LDL; D007555:Isoxazoles; C000610599:Lpar3 protein, mouse; D008246:Lysophospholipids; D011422:Propionates; D011973:Receptors, LDL; D049368:Receptors, Lysophosphatidic Acid; C000626582:LPAR1 protein, mouse; C032881:lysophosphatidic acid