PMID- 31210335
OWN - NLM
STAT- MEDLINE
DCOM- 20200925
LR  - 20200925
IS  - 2284-0729 (Electronic)
IS  - 1128-3602 (Linking)
VI  - 23
IP  - 11
DP  - 2019 Jun
TI  - Metformin inhibits LPS-induced inflammatory response in VSMCs by regulating TLR4 
      and PPAR-gamma.
PG  - 4988-4995
LID - 18090 [pii]
LID - 10.26355/eurrev_201906_18090 [doi]
AB  - OBJECTIVE: This study aims to explore whether the inhibitory role of metformin 
      could inhibit LPS-induced inflammatory response in vascular smooth muscle cells 
      (VSMCs) and its underlying mechanism. MATERIALS AND METHODS: VSMCs were extracted 
      from aorta of Sprague Dawley rats. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl 
      tetrazolium bromide) assay was performed to detect VSMCs viability after 
      treatment with different concentrations of metformin. Levels of monocyte 
      chemoattractant protein-1 (MCP-1), interleukin 6 (IL-6) and tumor necrosis 
      factor-alpha (TNF-alpha) in VSMCs were detected by ELISA (enzyme-linked immunosorbent 
      assay) and qRT-PCR (quantitative Real time-polymerase chain reaction). Protein 
      and mRNA levels of toll like receptor 4 (TLR4) and peroxisome proliferators 
      activated receptor gamma (PPAR-gamma) in VSMCs were detected by Western blot and qRT-PCR, 
      respectively. Finally, VSMCs were treated with the PPAR-gamma antagonist GW9662 and 
      inflammatory indicators in cells were detected. RESULTS: No significant 
      difference in VSMCs viability was found after 0-2 mM metformin treatment or 500 
      mug/L LPS induction for 24 h. After 500 mug/L LPS induction in VSMCs for 24 h, 
      levels of MCP-1, TNF-alpha and IL-6 were remarkably elevated. Both mRNA and protein 
      levels of TLR4 in VSMCs were upregulated after 500 mug/L LPS induction for 24 h, 
      which were remarkably reversed by the treatment of different concentrations of 
      metformin. Knockdown of TLR4 remarkably inhibited LPS-induced inflammatory 
      response in VSMCs, manifesting as decreased levels of MCP1, TNF-alpha and IL-6, which 
      were further downregulated after combination treatment of TLR4 knockdown and 20 
      mM metformin. Furthermore, both mRNA and protein levels of PPAR-gamma in VSMCs were 
      downregulated after 500 mug/L LPS induction for 24 h, which were remarkably 
      reversed by the treatment of different concentrations of metformin. GW9662 
      treatment resulted in elevated expressions of MCP-1, TNF-alpha and IL-6, which were 
      reversed by metformin treatment. CONCLUSIONS: Metformin can effectively inhibit 
      the mRNA and protein expressions of IL-6, MCP-1, and TNF-alpha in LPS-induced VSMCs. 
      The anti-inflammatory effects of metformin inhibit the inflammatory response 
      through downregulating rely on the downregulation of TLR4 expression and 
      upregulation ofng PPAR-gamma activity.
FAU - Qu, R-N
AU  - Qu RN
AD  - Department of Pharmacy, China-Japan Union Hospital of Jilin University, 
      Changchun, China. quruoning@163.com.
FAU - Qu, W
AU  - Qu W
LA  - eng
PT  - Journal Article
PL  - Italy
TA  - Eur Rev Med Pharmacol Sci
JT  - European review for medical and pharmacological sciences
JID - 9717360
RN  - 0 (Ccl2 protein, rat)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Il6 protein, rat)
RN  - 0 (Interleukin-6)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (PPAR gamma)
RN  - 0 (Tlr4 protein, rat)
RN  - 0 (Toll-Like Receptor 4)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 9100L32L2N (Metformin)
SB  - IM
MH  - Animals
MH  - Atherosclerosis/drug therapy/immunology
MH  - Cells, Cultured
MH  - Chemokine CCL2/immunology/metabolism
MH  - Down-Regulation/drug effects/immunology
MH  - Drug Evaluation, Preclinical
MH  - Endothelium, Vascular/immunology
MH  - Humans
MH  - Interleukin-6/immunology/metabolism
MH  - Lipopolysaccharides/immunology
MH  - Male
MH  - Metformin/*pharmacology/therapeutic use
MH  - Muscle, Smooth, Vascular/*cytology/drug effects/immunology
MH  - Myocytes, Smooth Muscle/*drug effects/immunology
MH  - PPAR gamma/metabolism
MH  - Primary Cell Culture
MH  - Rats
MH  - Signal Transduction/*drug effects/immunology
MH  - Toll-Like Receptor 4/metabolism
MH  - Tumor Necrosis Factor-alpha/immunology/metabolism
MH  - Up-Regulation/drug effects/immunology
EDAT- 2019/06/19 06:00
MHDA- 2020/09/26 06:00
CRDT- 2019/06/19 06:00
PHST- 2019/06/19 06:00 [entrez]
PHST- 2019/06/19 06:00 [pubmed]
PHST- 2020/09/26 06:00 [medline]
AID - 18090 [pii]
AID - 10.26355/eurrev_201906_18090 [doi]
PST - ppublish
SO  - Eur Rev Med Pharmacol Sci. 2019 Jun;23(11):4988-4995. doi: 
      10.26355/eurrev_201906_18090.