PMID- 38222824
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240116
IS  - 2081-3856 (Print)
IS  - 2081-6936 (Electronic)
IS  - 2081-6936 (Linking)
VI  - 14
IP  - 1
DP  - 2023 Jan 1
TI  - The BET inhibitor apabetalone decreases neuroendothelial proinflammatory 
      activation in vitro and in a mouse model of systemic inflammation.
PG  - 20220332
LID - 10.1515/tnsci-2022-0332 [doi]
LID - 20220332
AB  - Brain vascular inflammation is characterized by endothelial activation and immune 
      cell recruitment to the blood vessel wall, potentially causing a breach in the 
      blood - brain barrier, brain parenchyma inflammation, and a decline of cognitive 
      function. The clinical-stage small molecule, apabetalone, reduces circulating 
      vascular endothelial inflammation markers and improves cognitive scores in 
      elderly patients by targeting epigenetic regulators of gene transcription, 
      bromodomain and extraterminal proteins. However, the effect of apabetalone on 
      cytokine-activated brain vascular endothelial cells (BMVECs) is unknown. Here, we 
      show that apabetalone treatment of BMVECs reduces hallmarks of in vitro 
      endothelial activation, including monocyte chemoattractant protein-1 (MCP-1) and 
      RANTES chemokine secretion, cell surface expression of endothelial cell adhesion 
      molecule VCAM-1, as well as endothelial capture of THP-1 monocytes in static and 
      shear stress conditions. Apabetalone pretreatment of THP-1 downregulates cell 
      surface expression of chemokine receptors CCR1, CCR2, and CCR5, and of the VCAM-1 
      cognate receptor, integrin alpha4. Consequently, apabetalone reduces THP-1 
      chemoattraction towards soluble CCR ligands MCP-1 and RANTES, and THP-1 adhesion 
      to activated BMVECs. In a mouse model of brain inflammation, apabetalone counters 
      lipopolysaccharide-induced transcription of endothelial and myeloid cell markers, 
      consistent with decreased neuroendothelial inflammation. In conclusion, 
      apabetalone decreases proinflammatory activation of brain endothelial cells and 
      monocytes in vitro and in the mouse brain during systemic inflammation.
CI  - (c) 2023 the author(s), published by De Gruyter.
FAU - Wasiak, Sylwia
AU  - Wasiak S
AD  - Resverlogix Corp., Suite 300, 4820 Richard Road SW, Calgary, AB, T3e 6L1, Canada.
FAU - Fu, Li
AU  - Fu L
AD  - Resverlogix Corp., Suite 300, 4820 Richard Road SW, Calgary, AB, T3e 6L1, Canada.
FAU - Daze, Emily
AU  - Daze E
AD  - Resverlogix Corp., Suite 300, 4820 Richard Road SW, Calgary, AB, T3e 6L1, Canada.
FAU - Gilham, Dean
AU  - Gilham D
AD  - Resverlogix Corp., Suite 300, 4820 Richard Road SW, Calgary, AB, T3e 6L1, Canada.
FAU - Rakai, Brooke D
AU  - Rakai BD
AD  - Resverlogix Corp., Suite 300, 4820 Richard Road SW, Calgary, AB, T3e 6L1, Canada.
FAU - Stotz, Stephanie C
AU  - Stotz SC
AD  - Resverlogix Corp., Suite 300, 4820 Richard Road SW, Calgary, AB, T3e 6L1, Canada.
FAU - Tsujikawa, Laura M
AU  - Tsujikawa LM
AD  - Resverlogix Corp., Suite 300, 4820 Richard Road SW, Calgary, AB, T3e 6L1, Canada.
FAU - Sarsons, Chris D
AU  - Sarsons CD
AD  - Resverlogix Corp., Suite 300, 4820 Richard Road SW, Calgary, AB, T3e 6L1, Canada.
FAU - Studer, Deborah
AU  - Studer D
AD  - Department of Biomedical Engineering, Department of Physiology and Pharmacology, 
      Libin Cardiovascular Institute, University of Calgary, 2500 University Dr. NW, 
      Calgary, AB, T2N 1N4, Canada.
FAU - Rinker, Kristina D
AU  - Rinker KD
AD  - Department of Biomedical Engineering, Department of Physiology and Pharmacology, 
      Libin Cardiovascular Institute, University of Calgary, 2500 University Dr. NW, 
      Calgary, AB, T2N 1N4, Canada.
FAU - Jahagirdar, Ravi
AU  - Jahagirdar R
AD  - Resverlogix Corp., Suite 300, 4820 Richard Road SW, Calgary, AB, T3e 6L1, Canada.
FAU - Wong, Norman C W
AU  - Wong NCW
AD  - Resverlogix Corp., Suite 300, 4820 Richard Road SW, Calgary, AB, T3e 6L1, Canada.
FAU - Sweeney, Michael
AU  - Sweeney M
AD  - Resverlogix Corp., 535 Mission Street, 14th Floor, San Francisco, CA, 94105, USA.
FAU - Johansson, Jan O
AU  - Johansson JO
AD  - Resverlogix Corp., 535 Mission Street, 14th Floor, San Francisco, CA, 94105, USA.
FAU - Kulikowski, Ewelina
AU  - Kulikowski E
AD  - Resverlogix Corp., Suite 300, 4820 Richard Road SW, Calgary, AB, T3e 6L1, Canada.
LA  - eng
PT  - Journal Article
DEP - 20231231
PL  - Germany
TA  - Transl Neurosci
JT  - Translational neuroscience
JID - 101550327
PMC - PMC10787226
OTO - NOTNLM
OT  - blood-brain barrier
OT  - bromodomain
OT  - epigenetics
OT  - inflammation
OT  - microvascular disease
COIS- Conflict of interest: S.W., L.F, E.D., D.G., B.D.R., S.C.S, L.M.T., C.D.S., R.J., 
      J.O.J., M.S., N.C.W.W., and E.K. were employed by Resverlogix Corp. at the time 
      of the study and hold company's shares and stock options. All other authors state 
      no conflict of interest.
EDAT- 2024/01/15 06:43
MHDA- 2024/01/15 06:44
PMCR- 2023/12/31
CRDT- 2024/01/15 04:36
PHST- 2023/09/25 00:00 [received]
PHST- 2023/12/15 00:00 [revised]
PHST- 2023/12/19 00:00 [accepted]
PHST- 2024/01/15 06:44 [medline]
PHST- 2024/01/15 06:43 [pubmed]
PHST- 2024/01/15 04:36 [entrez]
PHST- 2023/12/31 00:00 [pmc-release]
AID - tnsci-2022-0332 [pii]
AID - 10.1515/tnsci-2022-0332 [doi]
PST - epublish
SO  - Transl Neurosci. 2023 Dec 31;14(1):20220332. doi: 10.1515/tnsci-2022-0332. 
      eCollection 2023 Jan 1.