Role of the LPC‐ATX‐LPA Axis in the Development of Endothelial Dysfunction

Abstract

IntroductionLysophosphatidylcoline (LPC) is a bioactive lipid component of low‐density lipoprotein (LDL) that plays an important role in the development of atherosclerosis. Based on literature data, LPC causes endothelial dysfunction through decreasing NO bioavailability, however, the underlying mechanisms are not completely understood. LPC can be hydrolyzed into LPA by the cell secreted enzyme, autotaxin (ATX). Our aim was to investigate the role of the LPC‐ATX‐LPA axis in the development of endothelial dysfunction.MethodsMyographic measurements were performed on thoracic aorta segments isolated from male, adult C57/Bl6 mice. We examined the effect of 18:1 LPC (10 μM) on the NO‐dependent vasorelaxation after a 20 min incubation. The vessels were pre‐contracted with phenilephrine (PE), subsequently increasing concentrations of acetyl‐choline (ACh) were added to evoke vasorelaxation. Some of the vessels were pre‐treated with the ATX inhibitor BMP‐22 (10 μM) or the LPA1,3 antagonist Ki16425 (10 μM). FS‐3 substrate assay was used to measure ATX activity of the aortic tissue.ResultsLPC significantly attenuated ACh‐induced vasorelaxation without influencing the effect of the NO‐donor sodium nitroprusside. Interestingly, LPC‐induced suppression of the endothelium‐dependent vasorelaxation was more severe in the proximal, than the distal aorta that is more prone to develop atherosclerotic plaques. The ATX inhibitor BMP‐22 decreased the endothelial dysfunction and its protective effect was proved to be more pronounced in the proximal as compared to the distal segments. In addition, FS‐3 assay measurement for ATX activity showed higher activity in the proximal, than the distal part of the aorta. The LPA1,3 receptor inhibitor Ki16425 also reduced the effect of LPC in the proximal but not in the distal aorta.ConclusionsOur study shows that ATX and LPA are involved in LPC‐induced endothelial dysfunction. The results suggest that in this process LPA acts through LPA1 and / or LPA3 receptors. According to the literature the development of atherosclerosis is faster and more severe on the proximal segment of the thoracic aorta, therefore the LPC‐ATX‐LPA system is likely to contribute to the progression of the disease.Support or Funding InformationSupported by the Hungarian NRDIO (OTKA K‐112964, K‐125174 and NVKP_16‐1‐2016‐0042) as well as by the Higher Education Institutional Excellence Programme of the Ministry of Human Capacities in Hungary, within the framework of the Molecular Biology thematic programme of the Semmelweis University and by the EFOP‐3.6.3‐VEKOP‐16‐2017‐00009 grant.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.