PMID- 32012810
OWN - NLM
STAT- MEDLINE
DCOM- 20201104
LR  - 20201104
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 21
IP  - 3
DP  - 2020 Jan 28
TI  - FGF21 Protects against Aggravated Blood-Brain Barrier Disruption after Ischemic 
      Focal Stroke in Diabetic db/db Male Mice via Cerebrovascular PPARgamma Activation.
LID - 10.3390/ijms21030824 [doi]
LID - 824
AB  - Recombinant fibroblast growth factor 21 (rFGF21) has been shown to be potently 
      beneficial for improving long-term neurological outcomes in type 2 diabetes 
      mellitus (T2DM) stroke mice. Here, we tested the hypothesis that rFGF21 protects 
      against poststroke blood-brain barrier (BBB) damage in T2DM mice via peroxisome 
      proliferator-activated receptor gamma (PPARgamma) activation in cerebral 
      microvascular endothelium. We used the distal middle cerebral occlusion (dMCAO) 
      model in T2DM mice as well as cultured human brain microvascular endothelial 
      cells (HBMECs) subjected to hyperglycemic and inflammatory injury in the current 
      study. We detected a significant reduction in PPARgamma DNA-binding activity in the 
      brain tissue and mRNA levels of BBB junctional proteins and PPARgamma-targeting gene 
      CD36 and FABP4 in cerebral microvasculature at 24 h after stroke. Ischemic stroke 
      induced a massive BBB leakage two days after stroke in T2DM mice compared to in 
      their lean controls. Importantly, all abnormal changes were significantly 
      prevented by rFGF21 administration initiated at 6 h after stroke. Our in vitro 
      experimental results also demonstrated that rFGF21 protects against hyperglycemia 
      plus interleukin (IL)-1beta-induced transendothelial permeability through 
      upregulation of junction protein expression in an FGFR1 activation and PPARgamma 
      activity elevation-dependent manner. Our data suggested that rFGF21 has strong 
      protective effects on acute BBB leakage after diabetic stroke, which is partially 
      mediated by increasing PPARgamma DNA-binding activity and mRNA expression of BBB 
      junctional complex proteins. Together with our previous investigations, rFGF21 
      might be a promising candidate for treating diabetic stroke.
FAU - Jiang, Yinghua
AU  - Jiang Y
AUID- ORCID: 0000-0002-7344-7028
AD  - Clinical Neuroscience Research Center, Department of Neurosurgery, School of 
      Medicine, Tulane University, New Orleans, LA 70112, USA.
FAU - Lin, Li
AU  - Lin L
AD  - Neuroprotection Research Laboratory, Department of Radiology and Neurology, 
      Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, 
      USA.
FAU - Liu, Ning
AU  - Liu N
AD  - Clinical Neuroscience Research Center, Department of Neurosurgery, School of 
      Medicine, Tulane University, New Orleans, LA 70112, USA.
FAU - Wang, Qingzhi
AU  - Wang Q
AD  - Clinical Neuroscience Research Center, Department of Neurosurgery, School of 
      Medicine, Tulane University, New Orleans, LA 70112, USA.
FAU - Yuan, Jing
AU  - Yuan J
AD  - Clinical Neuroscience Research Center, Department of Neurosurgery, School of 
      Medicine, Tulane University, New Orleans, LA 70112, USA.
FAU - Li, Yadan
AU  - Li Y
AD  - Clinical Neuroscience Research Center, Department of Neurosurgery, School of 
      Medicine, Tulane University, New Orleans, LA 70112, USA.
FAU - Chung, Kelly K
AU  - Chung KK
AD  - Neuroprotection Research Laboratory, Department of Radiology and Neurology, 
      Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, 
      USA.
FAU - Guo, Shuzhen
AU  - Guo S
AUID- ORCID: 0000-0003-0627-5278
AD  - Neuroprotection Research Laboratory, Department of Radiology and Neurology, 
      Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, 
      USA.
FAU - Yu, Zhanyang
AU  - Yu Z
AD  - Neuroprotection Research Laboratory, Department of Radiology and Neurology, 
      Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, 
      USA.
FAU - Wang, Xiaoying
AU  - Wang X
AD  - Clinical Neuroscience Research Center, Department of Neurosurgery, School of 
      Medicine, Tulane University, New Orleans, LA 70112, USA.
LA  - eng
GR  - R01 NS099539/NS/NINDS NIH HHS/United States
GR  - R01 NS099539/NH/NIH HHS/United States
PT  - Journal Article
DEP - 20200128
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (PPAR gamma)
RN  - 0 (Pparg protein, mouse)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Tight Junction Proteins)
RN  - 0 (fibroblast growth factor 21)
RN  - 62031-54-3 (Fibroblast Growth Factors)
SB  - IM
MH  - Animals
MH  - Blood-Brain Barrier/*metabolism
MH  - Cells, Cultured
MH  - Diabetes Mellitus, Experimental/complications/genetics/*metabolism
MH  - Diabetes Mellitus, Type 2/complications/genetics/*metabolism
MH  - Endothelial Cells/cytology/drug effects/metabolism
MH  - Fibroblast Growth Factors/*administration & dosage/pharmacology
MH  - Gene Expression Regulation/drug effects
MH  - Humans
MH  - Male
MH  - Mice
MH  - PPAR gamma/*metabolism
MH  - Primary Cell Culture
MH  - Recombinant Proteins/administration & dosage/pharmacology
MH  - Stroke/*drug therapy/genetics/metabolism
MH  - Tight Junction Proteins/genetics/metabolism
PMC - PMC7037567
OTO - NOTNLM
OT  - Db/db mouse
OT  - blood-brain barrier
OT  - fibroblast growth factor 21
OT  - focal ischemic stroke
OT  - human brain microvascular endothelial cell
OT  - type 2 diabetes
COIS- The authors declare no conflict of interest.
EDAT- 2020/02/06 06:00
MHDA- 2020/11/05 06:00
PMCR- 2020/02/01
CRDT- 2020/02/05 06:00
PHST- 2020/01/10 00:00 [received]
PHST- 2020/01/24 00:00 [revised]
PHST- 2020/01/26 00:00 [accepted]
PHST- 2020/02/05 06:00 [entrez]
PHST- 2020/02/06 06:00 [pubmed]
PHST- 2020/11/05 06:00 [medline]
PHST- 2020/02/01 00:00 [pmc-release]
AID - ijms21030824 [pii]
AID - ijms-21-00824 [pii]
AID - 10.3390/ijms21030824 [doi]
PST - epublish
SO  - Int J Mol Sci. 2020 Jan 28;21(3):824. doi: 10.3390/ijms21030824.