doi: 10.1161/CIRCULATIONAHA.106.667196
(Circulation. 2007;115:e393.)
© 2007 American Heart Association, Inc.
Correspondence |
Letter by Xia Regarding Article, "High-Density Lipoproteins and Their Constituent, Sphingosine-1-Phosphate, Directly Protect the Heart Against Ischemia/Reperfusion Injury In Vivo via the S1P3 Lysophospholipid Receptor"
National Heart Foundation Career Development Fellowship Signal Transduction Laboratory Centenary Institute, Faculty of Medicine The University of Sydney Sydney, Australia
I read with interest the study by Theilmeier and colleagues1 reporting that high-density lipoproteins (HDL) and their constituent, sphingosine 1-phosphate (S1P), directly protect the heart against ischemia/reperfusion injury via the S1P3 receptor. From their observations, the authors conclude that S1P/S1P3 are responsible for the atheroprotective effects of HDL.
S1P is constitutively present in plasma or serum at a concentration that is 20- to 100-fold higher than its Kd value to the receptors, with more than 50% of the S1P bound to HDL.2 In this respect, HDL could function either as a carrier of S1P to facilitate its bioactivity or as a scavenger to neutralize it. Indeed, S1P bound to HDL has been shown to be both biologically active and inactive under various circumstances. Interestingly, S1P also seems to have opposing effects that mediate anti- or proinflammatory and vasorelaxant or vasoconstrictive reactions in vasculature.3 This is thought to depend on the differential expression/function of the cell-surface S1P-receptor subtypes and undefined intracellular effectors of S1P. Additionally, reconstituted HDL that does not contain S1P has antiatherogenic and antiinflammatory effects similar to those of native HDL, both in vitro and in vivo. Furthermore, we found that adhesion molecule expression, induced by 2 to 5 µmol/L S1P, was inhibited by either reconstituted or native HDL,4 suggesting that S1P is not required for the antiinflammatory effect of HDL.
To accept the concept that HDL functions through the S1P/S1P3 signaling pathway, as proposed by Theilmeier et al,1 a number of questions require further attention. First, is there a significant change in the levels and/or the bioactivity of S1P in blood after a single intravenous administration of HDL or even S1P? S1P has a short half-life (approximately 2 hours) and is easily degraded. Second, is HDL-bound S1P able to bind to and activate S1P3 directly? Third, does a deficiency of S1P3 per se influence the reperfusion injury in S1P3-/- mice? Finally, why does S1P that decreases myocardial perfusion, as the authors have previously reported,5 have a similar protective effect against reperfusion injury as HDL, which increases myocardial perfusion, through the same S1P3 receptor? By addressing these questions, we may obtain a greater understanding of the role of S1P/S1P3 in atheroprotection and of its involvement in the functional properties of HDL—namely, are they carriers or scavengers of S1P?
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Disclosures
None.
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 Top References |
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1. Theilmeier G, Schmidt C, Herrmann J, Keul P, Schafers M, Herrgott I, Mersmann J, Larmann J, Hermann S, Stypmann J, Schober O, Hildebrand R, Schulz R, Heusch G, Haude M, von Wnuck Lipinski K, Herzog C, Schmitz M, Erbel R, Chun J, Levkau B. High-density lipoproteins and their constituent, sphingosine-1-phosphate, directly protect the heart against ischemia/reperfusion injury in vivo via the S1P3 lysophospholipid receptor. Circulation. 2006; 114: 1403–1409.
2. Murata N, Sato K, Kon J, Tomura H, Yanagita M, Kuwabara A, Ui M, Okajima F. Interaction of sphingosine 1-phosphate with plasma components, including lipoproteins, regulates the lipid receptor-mediated actions. Biochem J. 2000; 352: 809–815.[CrossRef][Medline] [Order article via Infotrieve]
3. Saba JD, Hla T. Point-counterpoint of sphingosine 1-phosphate metabolism. Circ Res. 2004; 94: 724–734.
4. Xia P, Vadas MA, Rye KA, Barter PJ, Gamble JR. High density lipoproteins (HDL) interrupt the sphingosine kinase signaling pathway. A possible mechanism for protection against atherosclerosis by HDL. J Biol Chem. 1999; 274: 33143–33147.
5. Levkau B, Hermann S, Theilmeier G, van der Giet M, Chun J, Schober O, Schafers M. High-density lipoprotein stimulates myocardial perfusion in vivo. Circulation. 2004; 110: 3355–3359.
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