PMID- 30854968
OWN - NLM
STAT- MEDLINE
DCOM- 20200609
LR  - 20200609
IS  - 1875-5666 (Electronic)
IS  - 1566-5240 (Linking)
VI  - 19
IP  - 2
DP  - 2019
TI  - Adeno-associated Virus 9-mediated Small RNA Interference of TLR4 Alleviates 
      Myocardial Ischemia and Reperfusion Injury by Inhibition of the NF-kappaB and MAPK 
      Signaling Pathways in Rats.
PG  - 127-135
LID - 10.2174/1566524019666190311122521 [doi]
AB  - BACKGROUND: Despite intensive investigation, effective therapeutic procedures for 
      myocardial I/R injury are still in demand. OBJECTIVE: To explore the effect of 
      adeno-associated virus 9 (AAV9)-mediated small interfering RNA targeting TLR4 in 
      the treatment of myocardial ischemia and reperfusion (I/R) injury and its 
      influence on the NF-kappaB and MAPK signaling pathways. METHODS: Rats were divided 
      into 3 groups, namely, the sham, AAV9-siRNA control, and AAV9-TLR4 siRNA groups. 
      siRNA solution or normal saline was injected through the tail vain. The rat 
      myocardial I/R injury model was then established. HE staining and TUNEL staining 
      were applied to compare the pathological changes in cardiomyocytes in the three 
      groups. Immunohistochemical staining and western blotting were utilized to detect 
      TLR4 expression under siRNA interference. Serum inflammatory factor (IL-1beta, 
      TNF-alpha) expression was determined by an ELISA commercial kit. Key proteins in the 
      MAPK (p38, JNK 1/2) and NF-kappaB (p65) signaling pathways were determined to 
      identify the TLR4 siRNA functional mechanism. RESULTS: Fluorescence microscopic 
      images of the myocardium indicated that AAV9- mediated siRNA was efficiently 
      transfected into the myocardium, and the infarcted size after I/R injury was 
      decreased by AAV9-TLR4 siRNA when compared with negative control rats (P<0.05). 
      TLR4 protein expression was significantly decreased by siRNA interference 
      (P<0.001). Apoptosis-related factor BCL-2 expression was increased in the TLR4 
      gene silencing group, whereas Bax expression was decreased. The Bax/BCL-2 ratio 
      was also decreased, demonstrating a protective effect for cardiomyocytes. 
      Inflammatory factors were lower in the TLR4 gene silencing group than in the 
      siRNA control group (P<0.001). The MAPK and NF-kappaB signaling pathways were 
      activated in myocardial I/R injury; however, the primary proteins in these two 
      signaling pathways were downregulated upon interference of TLR4 siRNA, with 
      significant differences (P<0.05). CONCLUSION: AAV9-TLR4 siRNA has a positive 
      effect on myocardial I/R injury by inhibiting the MAPK and NF-kappaB signaling 
      pathways and can be used as a potential therapeutic method for myocardial I/R 
      injury.
CI  - Copyright(c) Bentham Science Publishers; For any queries, please email at 
      epub@benthamscience.net.
FAU - Xu, Ting
AU  - Xu T
AD  - Harbin Medical University, Harbin, China.
FAU - Zhang, Kuikui
AU  - Zhang K
AD  - Department of Cardiology, First Affiliated Hospital, Heilongjiang University of 
      Chinese Medicine, Harbin, China.
FAU - Kan, Fuqiang
AU  - Kan F
AD  - Harbin Medical University, Harbin, China.
FAU - Li, Fengqin
AU  - Li F
AD  - Harbin Medical University, Harbin, China.
FAU - Yu, Bo
AU  - Yu B
AD  - Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical 
      University, Harbin, China.
FAU - Du, Wenjuan
AU  - Du W
AD  - Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical 
      University, Harbin, China.
FAU - Nie, Honggang
AU  - Nie H
AD  - Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical 
      University, Harbin, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Netherlands
TA  - Curr Mol Med
JT  - Current molecular medicine
JID - 101093076
RN  - 0 (NF-kappa B)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Tlr4 protein, rat)
RN  - 0 (Toll-Like Receptor 4)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - Dependovirus/*genetics
MH  - Gene Silencing
MH  - Male
MH  - Mitogen-Activated Protein Kinases/*antagonists & inhibitors
MH  - Myocardial Ischemia/genetics/pathology/*therapy
MH  - Myocardial Reperfusion Injury/genetics/pathology/*therapy
MH  - NF-kappa B/*antagonists & inhibitors
MH  - RNA, Small Interfering/*genetics
MH  - Rats
MH  - Rats, Wistar
MH  - Toll-Like Receptor 4/*antagonists & inhibitors/genetics
OTO - NOTNLM
OT  - AAV9-TLR4 siRNA
OT  - MAPK
OT  - Myocardial I/R injury
OT  - NF-kappaB
OT  - inflammatory
OT  - ischemia.
EDAT- 2019/03/12 06:00
MHDA- 2020/06/10 06:00
CRDT- 2019/03/12 06:00
PHST- 2018/08/31 00:00 [received]
PHST- 2019/02/27 00:00 [revised]
PHST- 2019/03/01 00:00 [accepted]
PHST- 2019/03/12 06:00 [pubmed]
PHST- 2020/06/10 06:00 [medline]
PHST- 2019/03/12 06:00 [entrez]
AID - CMM-EPUB-97211 [pii]
AID - 10.2174/1566524019666190311122521 [doi]
PST - ppublish
SO  - Curr Mol Med. 2019;19(2):127-135. doi: 10.2174/1566524019666190311122521.