Srividya Velagapudi1, Lucia Rohrer1, Francesco Poti2,3, Jerzy-Roch Nofer3,4,5, Arnold von Eckardstein1, Renate Feuerborn4, Damir Perisa1, Dongdong Wang1, Grigorios Panteloglou1, Anton Potapenko1, Mustafa Yalcinkaya1, Andreas J Hülsmeier1, Bettina Hesse6, Alexander Lukasz6, Mingxia Liu7, John S Parks7, Christina Christoffersen8,9, Markus Stoffel10, Manuela Simoni3. 1. Institute of Clinical Chemistry, University of Zurich and University Hospital of Zurich, Switzerland (S.V., L.R., D.P., D.W., G.P., A.P., M.Y., A.J.H., A.v.E.). 2. Unit of Neurosciences, Department of Medicine and Surgery, University of Parma, Italy (F.P.). 3. Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Italy (F.P., M. Simoni, J.-R.N.). 4. Central Laboratory Facility, University Hospital of Münster, Germany (R.F., J.-R.N.). 5. Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Germany (J.-R.N.). 6. Department of Medicine D, Division of General Internal Medicine, Nephrology, and Rheumatology, University Hospital Münster, Germany (B.H., A.L.). 7. Department of Internal Medicine/Section of Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC (M.L., J.S.P.). 8. Department of Biomedical Science, University of Copenhagen, Denmark (C.C.). 9. Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark (C.C.). 10. Institute of Molecular Health Sciences, ETH Zurich, Switzerland (M. Stoffel).
Abstract
Objective: ApoM enriches S1P (sphingosine-1-phosphate) within HDL (high-density lipoproteins) and facilitates the activation of the S1P1 (S1P receptor type 1) by S1P, thereby preserving endothelial barrier function. Many protective functions exerted by HDL in extravascular tissues raise the question of how S1P regulates transendothelial HDL transport. Approach and Results: HDL were isolated from plasma of wild-type mice, Apom knockout mice, human apoM transgenic mice or humans and radioiodinated to trace its binding, association, and transport by bovine or human aortic endothelial cells. We also compared the transport of fluorescently-labeled HDL or Evans Blue, which labels albumin, from the tail vein into the peritoneal cavity of apoE-haploinsufficient mice with (apoE-haploinsufficient mice with endothelium-specific knockin of S1P1) or without (control mice, ie, apoE-haploinsufficient mice without endothelium-specific knockin of S1P1) endothelium-specific knockin of S1P1. The binding, association, and transport of HDL from Apom knockout mice and human apoM-depleted HDL by bovine aortic endothelial cells was significantly lower than that of HDL from wild-type mice and human apoM-containing HDL, respectively. The binding, uptake, and transport of 125I-HDL by human aortic endothelial cells was increased by an S1P1 agonist but decreased by an S1P1 inhibitor. Silencing of SR-BI (scavenger receptor BI) abrogated the stimulation of 125I-HDL transport by the S1P1 agonist. Compared with control mice, that is, apoE-haploinsufficient mice without endothelium-specific knockin of S1P1, apoE-haploinsufficient mice with endothelium-specific knockin of S1P1 showed decreased transport of Evans Blue but increased transport of HDL from blood into the peritoneal cavity and SR-BI expression in the aortal endothelium. Conclusions: ApoM and S1P1 promote transendothelial HDL transport. Their opposite effect on transendothelial transport of albumin and HDL indicates that HDL passes endothelial barriers by specific mechanisms rather than passive filtration.
Objective: ApoM enriches S1P (sphingosine-1-phosphate) within HDL (high-density lipoproteins) and facilitates the activation of the S1P1 (S1P receptor type 1) by S1P, thereby preserving endothelial barrier function. Many protective functions exerted by HDL in extravascular tissues raise the question of how S1P regulates transendothelial HDL transport. Approach and Results: HDL were isolated from plasma of wild-type mice, Apom knockout mice, human apoM transgenic mice or humans and radioiodinated to trace its binding, association, and transport by bovine or human aortic endothelial cells. We also compared the transport of fluorescently-labeled HDL or Evans Blue, which labels albumin, from the tail vein into the peritoneal cavity of apoE-haploinsufficient mice with (apoE-haploinsufficient mice with endothelium-specific knockin of S1P1) or without (control mice, ie, apoE-haploinsufficient mice without endothelium-specific knockin of S1P1) endothelium-specific knockin of S1P1. The binding, association, and transport of HDL from Apom knockout mice and human apoM-depleted HDL by bovine aortic endothelial cells was significantly lower than that of HDL from wild-type mice and human apoM-containing HDL, respectively. The binding, uptake, and transport of 125I-HDL by human aortic endothelial cells was increased by an S1P1 agonist but decreased by an S1P1 inhibitor. Silencing of SR-BI (scavenger receptor BI) abrogated the stimulation of 125I-HDL transport by the S1P1 agonist. Compared with control mice, that is, apoE-haploinsufficient mice without endothelium-specific knockin of S1P1, apoE-haploinsufficient mice with endothelium-specific knockin of S1P1 showed decreased transport of Evans Blue but increased transport of HDL from blood into the peritoneal cavity and SR-BI expression in the aortal endothelium. Conclusions: ApoM and S1P1 promote transendothelial HDL transport. Their opposite effect on transendothelial transport of albumin and HDL indicates that HDL passes endothelial barriers by specific mechanisms rather than passive filtration.
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