PMID- 30773606
OWN - NLM
STAT- MEDLINE
DCOM- 20200511
LR  - 20200511
IS  - 1573-7365 (Electronic)
IS  - 0885-7490 (Linking)
VI  - 34
IP  - 3
DP  - 2019 Jun
TI  - Expression and regulation of miR-449a and AREG in cerebral ischemic injury.
PG  - 821-832
LID - 10.1007/s11011-019-0393-9 [doi]
AB  - Rodent focal ischemia models are widely used to mimic and examine human strokes. 
      To the best of our knowledge, no investigation has systematically examined the 
      expression changes of microRNA (miR)-449a and Amphiregulin (AREG) as well as 
      their biological relationship during middle cerebral artery occlusion (MCAO) and 
      oxygen and glucose deprivation/reperfusion (OGD/R). The present study examined 
      the histological and behavioral outcomes of MCAO and the function of miR-449a and 
      AREG in cerebral ischemic injury. Rats were subjected to 2 h MCAO, which was 
      followed by reperfusion. miR-449a and AREG were examined in the injury tissues of 
      MCAO rats and the OGD/R cell line by reverse transcription-quantitative 
      polymerase chain reaction. Protein expressions of AREG in the injury tissues of 
      MCAO rats was measured using an immunohistochemistry and the protein expression 
      levels of AREG, epidermal growth factor receptor (EGFR), phosphatidylinositol 
      3-kinase (PI3K)/ protein kinase B (Akt) and the phosphorylation level of Akt 
      (p-Akt) were analyzed by western blotting. Cell apoptosis was examined following 
      the knock down and subsequent overexpression of AREG in a human OGD/R neuronal 
      cell line by small interfering RNAs (siRNAs) and plasmid transfection. Luciferase 
      reporter assays were used to validate the target of miR-449a. The expression 
      changes and regulatory mechanisms of miR-449a and AREG in an ischemia/reperfusion 
      (I/R) injury model were examined in vivo and in vitro. The neurological deficit 
      score, brain edema volume, cerebral infarct area, and the number of apoptosis 
      cells in ischemic rats were all markedly elevated, than that in the control rats. 
      The expression of miR-449a was decreased and AREG was increased in the MCAO rats 
      and human OGD/R neuronal cell line. miR-449a inhibition or AREG overexpression in 
      OGD/R cells resulted in a significant decrease in apoptotic cells, and AREG was 
      revealed to be one of the direct targets of miR-449a. Molecular recovery was 
      observed following transfection with miR-449a mimics and AREG knockdown in an 
      OGD/R model in vitro. The present study demonstrated that miR-449a was 
      downregulated while AREG was upregulated in cerebral ischemic injury, and the 
      recovery of neurological function can be obtained following the overexpression of 
      miR-449a and the knockdown of AREG in an I/R injury model. miR-449a functions in 
      ischemic stroke via directly targeting AREG. These findings suggest a novel 
      mechanism involving in cerebral I/R injury model and may aid investigators in 
      gaining a deeper understanding of strokes in a clinical setting.
FAU - Yu, Yanhui
AU  - Yu Y
AD  - Department of Neurology, Affiliated Hospital of ChiFeng University, ChiFeng, 
      024000, China.
FAU - Zhang, Xiuhui
AU  - Zhang X
AD  - Department of Preventive Medicine, ChiFeng University, ChiFeng, 024000, China.
FAU - Han, Zhengmin
AU  - Han Z
AD  - Department of Neurology, Affiliated Hospital of ChiFeng University, ChiFeng, 
      024000, China.
FAU - Zhao, Weili
AU  - Zhao W
AD  - Department of Neurology, Affiliated Hospital of ChiFeng University, ChiFeng, 
      024000, China.
FAU - Zhang, Limin
AU  - Zhang L
AUID- ORCID: 0000-0001-9073-0557
AD  - Department of Ophthalmology, Affiliated Hospital of ChiFeng University, ChiFeng, 
      024000, China. z120715@126.com.
AD  - Department of Ophthalmology, Affiliated Hospital of ChiFeng University, No.4, 
      Third section, East Garden Road, Hongshan District, Chifeng, 024005, Inner 
      Mongolia, China. z120715@126.com.
LA  - eng
PT  - Journal Article
DEP - 20190218
PL  - United States
TA  - Metab Brain Dis
JT  - Metabolic brain disease
JID - 8610370
RN  - 0 (Amphiregulin)
RN  - 0 (MIRN449 microRNA, rat)
RN  - 0 (MicroRNAs)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Amphiregulin/*metabolism
MH  - Animals
MH  - Brain/drug effects/metabolism
MH  - Brain Ischemia/*metabolism
MH  - Down-Regulation
MH  - Glucose/metabolism
MH  - Infarction, Middle Cerebral Artery/metabolism
MH  - Male
MH  - MicroRNAs/*genetics
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Rats, Sprague-Dawley
MH  - Reperfusion Injury/metabolism
MH  - Stroke/*metabolism
MH  - Up-Regulation
OTO - NOTNLM
OT  - AREG
OT  - Ischemia
OT  - MCAO
OT  - OGD/R
OT  - Stroke
OT  - miR-449a
EDAT- 2019/02/19 06:00
MHDA- 2020/05/12 06:00
CRDT- 2019/02/19 06:00
PHST- 2018/12/05 00:00 [received]
PHST- 2019/01/30 00:00 [accepted]
PHST- 2019/02/19 06:00 [pubmed]
PHST- 2020/05/12 06:00 [medline]
PHST- 2019/02/19 06:00 [entrez]
AID - 10.1007/s11011-019-0393-9 [pii]
AID - 10.1007/s11011-019-0393-9 [doi]
PST - ppublish
SO  - Metab Brain Dis. 2019 Jun;34(3):821-832. doi: 10.1007/s11011-019-0393-9. Epub 
      2019 Feb 18.