Inhibition of lysophosphatidic acid receptors 1 and 3 attenuates atherosclerosis development in LDL-receptor deficient mice

• Published in: Scientific reports Vol. 6; no. 1; p. 37585
• Main Authors: Kritikou, Eva, van Puijvelde, Gijs H M, van der Heijden, Thomas, van Santbrink, Peter J, Swart, Maarten, Schaftenaar, Frank H, Kröner, Mara J, Kuiper, Johan, Bot, Ilze
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 24.11.2016
• Subjects: Apoptosis; Arteriosclerosis; Atherosclerosis; CD25 antigen; CD4 antigen; Cholesterol; Foxp3 protein; Immunoregulation; Inflammation; Low density lipoprotein; Lymphocytes T; Lysophosphatidic acid; Lysophosphatidic acid receptors; Monocyte chemoattractant protein 1; Monocytes; Plaques; Rodents
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep37585

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 LPA 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 LPA antagonism using the small molecule Ki16425. We show that LPA inhibition 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 LPA blockade enhanced the percentage of non-inflammatory, Ly6C monocytes and CD4 CD25 FoxP3 T-regulatory cells. Finally, we demonstrate that LPA antagonism mildly reduced plasma LDL cholesterol levels. Therefore, pharmacological inhibition of LPA receptors may prove a promising approach to diminish atherosclerosis development.