Anna Janovicz1, Nóra Melinda Kerkovits1, Alíz Majer1, Lili Balogh1, Andrea Balogh1, Gábor Tigyi1,2, Éva Ruisanchez1, Zoltán Benyó1
1Institute of Clinical Experimental Research, Semmelweis University Budapest, Hungary
2Department of Physiology, University of Tennessee Health Science Center Memphis, TN, USA
Introduction and aims: Lysophosphatidylcholine (LPC) is a major phospholipid component of the oxidized low-density lipoprotein which has been implicated in the pathogenesis of atherosclerosis. An early step of this process is the decrease of endothelial NO bioavailability that leads to reduced ACh-dependent vasorelaxation. According to literature, LPC can evoke endothelial dysfunction, however the underlying mechanisms are controversial. Although LPC can be hydrolised into LPA by the cell-surface enzyme autotaxin (ATX), the involvement of this pathway in the development of LPC-induced endothelial dysfunction has not been addressed yet.
Methods: Myographic experiments were performed on thoracic aorta segments isolated from adult male C57/Bl6 mice. The effect of LPC on the ACh-dependent vasorelaxation was studied after a 20 min incubation. Some of the vessels were pre-treated with the ATX inhibitor BMP-22, the LPA1,3 receptor antagonist Ki16425, or AM095, a selective inhibitor of LPA1 receptor. FS-3 substrate assay was used to measure the ATX activity of the aortic tissue.
Results: LPC significantly attenuated the ACh-induced vasorelaxation and this effect was more severe in the proximal, than the distal aorta. The ATX inhibitor BMP-22 reduced the effect of LPC only in the proximal aorta. In addition, ATX activity was higher in the proximal, as compared to the distal part of the aorta. Ki16425 and AM095 also reduced the endothelial dysfunction and these effects appeared to be more pronounced in the proximal, than in the distal aorta.
Conclusions: Our study shows that ATX and LPA are involved in LPC-induced endothelial dysfunction. The results suggest that in this process LPA acts through LPA1 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.
Doctoral School: Basic and Translational Medicine
Program: The Mechanisms of Normal and Pathologic Functions of the Circulatory System
Supervisor: Zoltán Benyó
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