High-Density Lipoprotein–Associated Apolipoprotein M Limits Endothelial Inflammation by Delivering Sphingosine-1-Phosphate to the Sphingosine-1-Phosphate Receptor 1

Abstract Objectives High density lipoprotein (HDL) has been reported to show protective effects against cell death. Apolipoprotein M (ApoM) in HDL can bind with sphingosine-1-phosphate (S1P) and deliver S1P to target cells. This study aimed to evaluate the effects of HDL on astrocyte apoptosis after ischemic insult and determine the role of ApoM.Methods After ApoM-associated HDL (HDLapoM+) and ApoM-depleted HDL(HDLapoM-) were separated from mouse plasma, primary cultured mouse astrocytes were chellenged with oxygen-glucose deprivation followed by recovery in presence of HDLapoM+ or HDLapoM-. mRNA and protein samples were collected for biochemical analysis.Results The addition of HDLapoM+ attenuated apoptotic cell death in the astrocytes, but HDLapoM- did not show any effect. S1P receptor 1 (S1PR1) expression was upregulated, and specific S1PR1 inhibitor or genetic knockdown of S1pr1 abolished the protective effects. In addition, activation of Akt and ERK was induced by HDLapoM+ or free S1P, and pharmacological inhibition of Akt and ERK reduced the protection of HDLapoM+.Conclusions ApoM is essential for the protective effects of HDL, which depends on S1PR1 activation and downstream activation of Akt/ERK, Thus, ApoM may be a neuroprotective component in plasma.

Download Full-text

Apolipoprotein M in High Density Lipoprotein Protects Against Astrocyte Apoptosis Induced By Ischemic Insult Via Sphingosine 1-Phosphate Signaling

10.21203/rs.3.rs-216278/v1 ◽

2021 ◽

Author(s):

Xiaojia Huang ◽

Zhiqi Zhai ◽

Ting Zhou ◽

Chengju Sheng ◽

Chao Zhou ◽

...

Keyword(s):

Cell Death ◽

High Density Lipoprotein ◽

Apoptotic Cell ◽

Specific Inhibitor ◽

Density Lipoprotein ◽

High Density ◽

Protective Effects ◽

Ischemic Insult ◽

Apolipoprotein M ◽

Sphingosine 1 Phosphate

Abstract Apolipoprotein M (ApoM) has been reported to be contained in high density lipoprotein (HDL) and bound with sphingosine-1-phosphate (S1P). ApoM-associated HDL exerts protective effects against cell death. The aims of the study were to evaluate the effects of ApoM-associated HDL on astrocytes following ischemic insult. Primary cultured mouse astrocytes were treated with oxygen-glucose deprivation (OGD) followed by recovery. The astrocytes underwent apoptosis after treatment with OGD for 4 h and recovery for 24 h. The addition of HDL with ApoM attenuated apoptotic cell death, but HDL without ApoM did not show any effect. Free S1P or ApoM-bound S1P promoted cell survival and inhibited apoptosis. Only S1P receptor 1 (S1PR1) expression was upregulated and blockage of S1PR1 with specific inhibitor or genetic knockdown of S1pr1 abolished the protective effects. In addition, administration of ApoM containing HDL or free S1P induced activation of Akt and Erk in the astrocytes, and pharmacological inhibition of Akt and Erk rescued cell death after OGD treatment. Taken together, ApoM is required for the protective effects of HDL, which depends on delivery of S1P to S1PR1 by ApoM in HDL, indicating ApoM may be a neuroprotective constituent in plasma.

Download Full-text