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RapaLink-1 plays an antithrombotic role in antiphospholipid syndrome by improving autophagy both in vivo and vitro.

Abstract：

BACKGROUND:RapaLink-1 is a third generation mammalian target of rapamycin (mTOR) inhibitor and displays superior inhibitory effect on mTOR complex 1 (mTORC1). mTOR pathway is known to block autophagy and inhibition of it can protect thrombosis-related diseases including atherosclerosis, antiphospholipid syndrome (APS) and stroke. The objective of this study was to investigate whether RapaLink-1 could exert anti-thrombotic effects on APS via improving autophagy. METHODS:BALB/c mice were injected with monoclonal anti-beta-2-GPI (β2GPI) antibodies to induce APS in vivo, and anti-β2GPI antibodies together with anticardiolipin (aCL) antibodies in mice serum were assessed. The aortas of mice were isolated, and oil red and haematoxylin and eosin (HE) staining were used for thrombus morphology. The levels of LC3B and CD68 were quantified. Human monocyte cell line THP-1 was stimulated with oxidized low-density lipoprotein (ox-LDL) and treated with RapaLink-1 in vitro. The cell viability, LDH activity, apoptosis rate and rate of fate-positive cells were detected. LC3 expression was quantified by immunofluorescence. Western blot was utilized to assess the protein expression of LC3-І, LC3-П, Beclin-1 and p62. RESULTS:The size of arterial thrombus plaque together with the level of anti-β2GPI antibodies and aCL was reduced by RapaLink-1. Immunostaining protocols confirmed that the application of RapaLink-1 inhibited plaque initiation and progression while decreased the extent of macrophage infiltration and enhanced the autophagy process. In vitro cultured THP-1 macrophages exposed to ox-LDL study showed that RapaLink-1 prevented cell apoptosis and enhanced autophagy of macrophages, indicated by the increasing expression of autophagy-related protein and morphological character under electron microscopy. CONCLUSION:Our results revealed that Rapalink-1 has a potential to inhibit the formation of thrombus plaque in APS and these effects were dependent on facilitating cell autophagy both in vivo and in vitro.

journal_name

Biochem Biophys Res Commun

journal_title

Biochemical and biophysical research communications

authors

Mu F,Jiang Y,Ao F,Wu H,You Q,Chen Z

doi

10.1016/j.bbrc.2020.02.084

subject

Has Abstract

pub_date

2020-04-30 00:00:00

pages

384-391

issue

eissn

0006-291X

issn

1090-2104

pii

S0006-291X(20)30358-2

journal_volume

525

pub_type

杂志文章

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RapaLink-1 plays an antithrombotic role in antiphospholipid syndrome by improving autophagy both in vivo and vitro.