Response to Letter 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”
The question raised by Dr Xia is based on the hypothesis that plasma proteins “buffer” the large amounts of sphingosine 1-phosphate (S1P) present in plasma to prevent it from erroneously activating S1P receptors.1 Although reconstituted high-density lipoprotein (HDL) that does not contain S1P has numerous biological effects when administered in vivo, it is unknown whether and how rapidly it may actually acquire S1P from the plasma once it enters the circulation. Subsequently, such “S1P-charged” HDL may be partially responsible for the effects attributed to the original reconstituted HDL. In fact, preparations of reconstituted HDL loaded with S1P, and not reconstituted HDL alone, potently induce endothelial tube formation; both are similarly effective in promoting cholesterol efflux.2
In our opinion, the main question is not whether HDL carries or scavenges S1P, but what the biological effects of HDL-associated S1P are and how they contribute to known HDL effects. This leads us to answering the raised questions as follows: (1) both S1P and HDL clearly have biological effects in vivo after a single administration, suggesting a long-enough biological half-life3,4; (2) HDL-associated S1P activates S1P3 directly, because approximately 50% of the vasodilatory and 100% of the cardioprotective effect of HDL, respectively, are absent in S1P3-deficient mice3,4; (3) S1P3 deficiency does not influence reperfusion injury per se4; and (4) the beneficial effect of both S1P and HDL against reperfusion injury is attributable to their antiinflammatory, vasoprotective, and myocardioprotective properties and is mediated by S1P3.4 The stimulatory effect of HDL on myocardial perfusion5 may also contribute to cardioprotection during ischemia/reperfusion injury, while the putatively detrimental decrease in myocardial perfusion by S1P5 may be overwhelmed by its numerous beneficial effects.
Regarding the apparently divergent effects of S1P on arterial tone noted by Dr Xia, the particular arterial bed as well as its current tone are important: the same artery that contracts in response to S1P under basal conditions responds with vasodilation if precontracted by phenylephrine.3 Finally, the opposing effects of S1P on inflammation are attributable to the dual response of the endothelial cell: whereas proinflammatory effects have been observed at S1P concentrations 1000-fold higher than the Kd for its receptors and are not mediated by them, its antiinflammatory effects are elicited by physiological concentrations and are dependent on S1P receptors.6 Clearly, the cardiovascular effects of S1P in general and those of HDL-associated S1P in particular are a new and promising area of investigation, and they certainly bear many future surprises.
Matsuo Y, Miura SI, Kawamura A, Uehara Y, Rye KA, Saku K. Newly developed reconstituted high-density lipoprotein containing sphingosine-1-phosphate induces endothelial tube formation. Atherosclerosis. e-pub ahead of print November 20, 2006.
Nofer JR, van der Giet M, Tolle M, Wolinska I, von Wnuck Lipinski K, Baba HA, Tietge UJ, Godecke A, Ishii I, Kleuser B, Schafers M, Fobker M, Zidek W, Assmann G, Chun J, Levkau B. HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3. J Clin Invest. 2004; 113: 569–581.
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.
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.
Whetzel AM, Bolick DT, Srinivasan S, Macdonald TL, Morris MA, Ley K, Hedrick CC. Sphingosine-1 phosphate prevents monocyte/endothelial interactions in type 1 diabetic NOD mice through activation of the S1P1 receptor. Circ Res. 2006; 99: 731–739.