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Atherogenic properties of LDL particles modified by human group X secreted phospholipase A2 on human endothelial cell function

Sonia-Athina Karabina^*,1, Isabelle Brochériou^*,, Gilles Le Naour, Monique Agrapart^*, Hervé Durand^*, Michael Gelb, Gérard Lambeau^,2 and Ewa Ninio^*,2

^* INSERM, UMRS 525; Institut Fédératif CMV; Université Pierre et Marie Curie (UPMC-Paris 6) and Faculté de Médecine Pierre et Marie Curie;

Laboratoire Central d’Anatomie Pathologique du Groupe Hospitalier Pitié-Salpêtrière, Paris, France;

Departments of Chemistry and Biochemistry, University of Washington, Seattle, Washington, USA; and

IPMC, CNRS UMR 6097, Sophia Antipolis, Valbonne, France

¹Correspondence: INSERM UMRS 525, Faculté de Médecine Pierre et Marie Curie, 91, boulevard de l’Hôpital, 75634 Paris, France. E-mail: akarampi{at}chups.jussieu.fr

ABSTRACT

Increasing evidence suggests that secreted phospholipases A2 (sPLA2s) play an important role in the pathophysiology of atherosclerosis. Among sPLA2s, the human group X (hGX) enzyme has the highest catalytic activity toward phosphatidylcholine, one of the major phospholipid species of cell membranes and low-density lipoprotein (LDL). Our study examined the presence of hGX sPLA2 in human atherosclerotic lesions and investigated the ability of hGX modified LDL to alter human endothelial cell (HUVEC) function. Our results show that hGX sPLA2 is present in human atherosclerotic lesions and that the hydrolysis of LDL by hGX sPLA2 results in a modified particle that induces lipid accumulation in human monocyte-derived macrophages. Acting on endothelial cells, hGX-modified LDL activates the MAP kinase pathway, which leads to increased arachidonic acid release, increased expression of adhesion molecules on the surface of HUVEC, and increased adhesion of monocytes to HUVEC monolayers. Together, our data suggest that LDL modified by hGX, rather than hGX itself may have strong proinflammatory and proatherogenic properties, which could play an important role in the propagation of atherosclerosis.—Karabina, S. A., Brocheriou, I., Le Naour, G., Agrapart, M., Durand, H., Gelb, M., Lambeau, G., Ninio, E. Atherogenic properties of LDL particles modified by human group X secreted phospholipase A2 on human endothelial cell function.

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