Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M

Summary, in English

Protection of the endothelium is provided by circulating sphingosine-1-phosphate(S1P), which maintains vascular integrity. We show that HDL-associated S1P is bound specifically to both human and murine apolipoprotein M (apoM). Thus, isolated human ApoM(+) HDL contained S1P, whereas ApoM(-) HDL did not. Moreover, HDL in Apom(-/-) mice contains no S1P, whereas HDL in transgenic mice overexpressing human apoM has an increased S1P content. The 1.7-angstrom structure of the S1P-human apoM complex reveals that S1P interacts specifically with an amphiphilic pocket in the lipocalin fold of apoM. Human ApoM(+) HDL induced S1P(1) receptor internalization, downstream MAPK and Akt activation, endothelial cell migration, and formation of endothelial adherens junctions, whereas apoM(-) HDL did not. Importantly, lack of S1P in the HDL fraction of Apom(-/-) mice decreased basal endothelial barrier function in lung tissue. Our results demonstrate that apoM, by delivering S1P to the S1P(1) receptor on endothelial cells, is a vasculoprotective constituent of HDL.

• Författare: Christina Christoffersen; Hideru Obinata; Sunil Kumaraswamy; Sylvain Galvani; Josefin Ahnström; Madhumati Sevvana; Claudia Egerer-Sieber; Yves A. Muller; Timothy Hla; Lars B. Nielsen; Björn Dahlbäck
• Avdelning/ar: Klinisk kemi, Malmö
• Publiceringsår: 2011
• Språk: Engelska
• Sidor: 9613-9618
• Publikation/Tidskrift/Serie: Proceedings of the National Academy of Sciences
• Volym: 108
• Issue: 23
• Länkar: http://dx.doi.org/10.1073/pnas.1103187108
• Dokumenttyp: Artikel i tidskrift
• Förlag: National Academy of Sciences
• Ämne: Medicinal Chemistry
• Nyckelord: endothelial function; crystal structure; sphingolipids; vascular; permeability; atherosclerosis
• Status: Published
• Forskningsgrupp: Clinical Chemistry, Malmö
• ISBN/ISSN/Övrigt: ISSN: 1091-6490