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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 LU ; Mendez, Armando J.; Ruiz Garcia, Mario LU ; Castillo, Melanie; Hughes, Thomas A.; Dahlbäck, Björn LU and Goldberg, Ronald B. (2017) In Arteriosclerosis, Thrombosis, and Vascular Biology 37(6). p.1194-1205
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.... (More)

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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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
apolipoproteins, endothelium, lipoproteins, sphingolipids, tumor necrosis factor-alpha
in
Arteriosclerosis, Thrombosis, and Vascular Biology
volume
37
issue
6
pages
1194 - 1205
publisher
American Heart Association
external identifiers
  • scopus:85019732203
  • wos:000401947700025
ISSN
1079-5642
DOI
10.1161/ATVBAHA.117.309275
language
English
LU publication?
yes
id
8c2aee10-537e-4512-b77d-f63d3e34a5da
date added to LUP
2017-06-19 10:45:53
date last changed
2017-09-18 11:41:57
@article{8c2aee10-537e-4512-b77d-f63d3e34a5da,
  abstract     = {<p>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 S1P<sub>1</sub>-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.</p>},
  author       = {Frej, Cecilia and Mendez, Armando J. and Ruiz Garcia, Mario and Castillo, Melanie and Hughes, Thomas A. and Dahlbäck, Björn and Goldberg, Ronald B.},
  issn         = {1079-5642},
  keyword      = {apolipoproteins,endothelium,lipoproteins,sphingolipids,tumor necrosis factor-alpha},
  language     = {eng},
  month        = {06},
  number       = {6},
  pages        = {1194--1205},
  publisher    = {American Heart Association},
  series       = {Arteriosclerosis, Thrombosis, and Vascular Biology},
  title        = {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},
  url          = {http://dx.doi.org/10.1161/ATVBAHA.117.309275},
  volume       = {37},
  year         = {2017},
}