A Shift in ApoM/S1P between HDL-Particles in Women with Type 1 Diabetes Mellitus Is Associated with Impaired Anti-Inflammatory Effects of the ApoM/S1P Complex

Cecilia Frej, Armando J Mendez, Mario Ruiz, Melanie Castillo, Thomas A. Hughes, Björn Dahlbäck, Ronald B Goldberg

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Objective-Type 1 diabetes mellitus (T1D) patients have an increased risk of cardiovascular disease despite high levels of high-density lipoproteins (HDL). Apolipoprotein M (apoM) and its ligand sphingosine 1-phospate (S1P) exert many of the anti-inflammatory effects of HDL. We investigated whether apoM and S1P are altered in T1D and whether apoM and S1P are important for HDL functionality in T1D. Approach and Results-ApoM and S1P were quantified in plasma from 42 healthy controls and 89 T1D patients. HDL was isolated from plasma and separated into dense, medium-dense, and light HDL by ultracentrifugation. Primary human aortic endothelial cells were challenged with tumor necrosis factor-α in the presence or absence of isolated HDL. Proinflammatory adhesion molecules E-selectin and vascular cellular adhesion molecule-1 were quantified by flow cytometry. Activation of the S1P1-receptor was evaluated by analyzing downstream signaling targets and receptor internalization. There were no differences in plasma levels of apoM and S1P between controls and T1D patients, but the apoM/S1P complexes were shifted from dense to light HDL particles in T1D. ApoM/S1P in light HDL particles from women were less efficient in inhibiting expression of vascular cellular adhesion molecule-1 than apoM/S1P in denser particles. The light HDL particles were unable to activate Akt, whereas all HDL subfractions were equally efficient in activating Erk and receptor internalization. Conclusions-ApoM/S1P in light HDL particles were inefficient in inhibiting tumor necrosis factor-α-induced vascular cellular adhesion molecule-1 expression in contrast to apoM/S1P in denser HDL particles. T1D patients have a higher proportion of light particles and hence more dysfunctional HDL, which could contribute to the increased cardiovascular disease risk associated with T1D.

Original languageEnglish (US)
Pages (from-to)1194-1205
Number of pages12
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume37
Issue number6
DOIs
StatePublished - Jun 1 2017

Fingerprint

Sphingosine
HDL Lipoproteins
Type 1 Diabetes Mellitus
Anti-Inflammatory Agents
Apolipoproteins
Light
Blood Vessels
Cardiovascular Diseases
Tumor Necrosis Factor-alpha
Lysosphingolipid Receptors
E-Selectin
Ultracentrifugation
Flow Cytometry

Keywords

  • apolipoproteins
  • endothelium
  • lipoproteins
  • sphingolipids
  • tumor necrosis factor-alpha

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

A Shift in ApoM/S1P between HDL-Particles in Women with Type 1 Diabetes Mellitus Is Associated with Impaired Anti-Inflammatory Effects of the ApoM/S1P Complex. / Frej, Cecilia; Mendez, Armando J; Ruiz, Mario; Castillo, Melanie; Hughes, Thomas A.; Dahlbäck, Björn; Goldberg, Ronald B.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 37, No. 6, 01.06.2017, p. 1194-1205.

Research output: Contribution to journalArticle

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abstract = "Objective-Type 1 diabetes mellitus (T1D) patients have an increased risk of cardiovascular disease despite high levels of high-density lipoproteins (HDL). Apolipoprotein M (apoM) and its ligand sphingosine 1-phospate (S1P) exert many of the anti-inflammatory effects of HDL. We investigated whether apoM and S1P are altered in T1D and whether apoM and S1P are important for HDL functionality in T1D. Approach and Results-ApoM and S1P were quantified in plasma from 42 healthy controls and 89 T1D patients. HDL was isolated from plasma and separated into dense, medium-dense, and light HDL by ultracentrifugation. Primary human aortic endothelial cells were challenged with tumor necrosis factor-α in the presence or absence of isolated HDL. Proinflammatory adhesion molecules E-selectin and vascular cellular adhesion molecule-1 were quantified by flow cytometry. Activation of the S1P1-receptor was evaluated by analyzing downstream signaling targets and receptor internalization. There were no differences in plasma levels of apoM and S1P between controls and T1D patients, but the apoM/S1P complexes were shifted from dense to light HDL particles in T1D. ApoM/S1P in light HDL particles from women were less efficient in inhibiting expression of vascular cellular adhesion molecule-1 than apoM/S1P in denser particles. The light HDL particles were unable to activate Akt, whereas all HDL subfractions were equally efficient in activating Erk and receptor internalization. Conclusions-ApoM/S1P in light HDL particles were inefficient in inhibiting tumor necrosis factor-α-induced vascular cellular adhesion molecule-1 expression in contrast to apoM/S1P in denser HDL particles. T1D patients have a higher proportion of light particles and hence more dysfunctional HDL, which could contribute to the increased cardiovascular disease risk associated with T1D.",
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AU - Frej, Cecilia

AU - Mendez, Armando J

AU - Ruiz, Mario

AU - Castillo, Melanie

AU - Hughes, Thomas A.

AU - Dahlbäck, Björn

AU - Goldberg, Ronald B

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N2 - Objective-Type 1 diabetes mellitus (T1D) patients have an increased risk of cardiovascular disease despite high levels of high-density lipoproteins (HDL). Apolipoprotein M (apoM) and its ligand sphingosine 1-phospate (S1P) exert many of the anti-inflammatory effects of HDL. We investigated whether apoM and S1P are altered in T1D and whether apoM and S1P are important for HDL functionality in T1D. Approach and Results-ApoM and S1P were quantified in plasma from 42 healthy controls and 89 T1D patients. HDL was isolated from plasma and separated into dense, medium-dense, and light HDL by ultracentrifugation. Primary human aortic endothelial cells were challenged with tumor necrosis factor-α in the presence or absence of isolated HDL. Proinflammatory adhesion molecules E-selectin and vascular cellular adhesion molecule-1 were quantified by flow cytometry. Activation of the S1P1-receptor was evaluated by analyzing downstream signaling targets and receptor internalization. There were no differences in plasma levels of apoM and S1P between controls and T1D patients, but the apoM/S1P complexes were shifted from dense to light HDL particles in T1D. ApoM/S1P in light HDL particles from women were less efficient in inhibiting expression of vascular cellular adhesion molecule-1 than apoM/S1P in denser particles. The light HDL particles were unable to activate Akt, whereas all HDL subfractions were equally efficient in activating Erk and receptor internalization. Conclusions-ApoM/S1P in light HDL particles were inefficient in inhibiting tumor necrosis factor-α-induced vascular cellular adhesion molecule-1 expression in contrast to apoM/S1P in denser HDL particles. T1D patients have a higher proportion of light particles and hence more dysfunctional HDL, which could contribute to the increased cardiovascular disease risk associated with T1D.

AB - Objective-Type 1 diabetes mellitus (T1D) patients have an increased risk of cardiovascular disease despite high levels of high-density lipoproteins (HDL). Apolipoprotein M (apoM) and its ligand sphingosine 1-phospate (S1P) exert many of the anti-inflammatory effects of HDL. We investigated whether apoM and S1P are altered in T1D and whether apoM and S1P are important for HDL functionality in T1D. Approach and Results-ApoM and S1P were quantified in plasma from 42 healthy controls and 89 T1D patients. HDL was isolated from plasma and separated into dense, medium-dense, and light HDL by ultracentrifugation. Primary human aortic endothelial cells were challenged with tumor necrosis factor-α in the presence or absence of isolated HDL. Proinflammatory adhesion molecules E-selectin and vascular cellular adhesion molecule-1 were quantified by flow cytometry. Activation of the S1P1-receptor was evaluated by analyzing downstream signaling targets and receptor internalization. There were no differences in plasma levels of apoM and S1P between controls and T1D patients, but the apoM/S1P complexes were shifted from dense to light HDL particles in T1D. ApoM/S1P in light HDL particles from women were less efficient in inhibiting expression of vascular cellular adhesion molecule-1 than apoM/S1P in denser particles. The light HDL particles were unable to activate Akt, whereas all HDL subfractions were equally efficient in activating Erk and receptor internalization. Conclusions-ApoM/S1P in light HDL particles were inefficient in inhibiting tumor necrosis factor-α-induced vascular cellular adhesion molecule-1 expression in contrast to apoM/S1P in denser HDL particles. T1D patients have a higher proportion of light particles and hence more dysfunctional HDL, which could contribute to the increased cardiovascular disease risk associated with T1D.

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KW - lipoproteins

KW - sphingolipids

KW - tumor necrosis factor-alpha

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