PMID- 30100024
OWN - NLM
STAT- MEDLINE
DCOM- 20190610
LR  - 20191001
IS  - 1095-8673 (Electronic)
IS  - 0022-4804 (Print)
IS  - 0022-4804 (Linking)
VI  - 230
DP  - 2018 Oct
TI  - Simvastatin reduces the TLR4-induced inflammatory response in human aortic valve 
      interstitial cells.
PG  - 101-109
LID - S0022-4804(18)30297-X [pii]
LID - 10.1016/j.jss.2018.04.054 [doi]
AB  - BACKGROUND: Calcific aortic stenosis is a chronic inflammatory disease. 
      Proinflammatory stimulation via toll-like receptor 4 (TLR4) causes the aortic 
      valve interstitial cell (AVIC) to undergo phenotypic change. The AVIC first 
      assumes an inflammatory phenotype characterized by the production of inflammatory 
      mediators such as intercellular adhesion molecule-1 (ICAM-1), interleukin-8 
      (IL-8), and monocyte chemoattractant protein-1 (MCP-1). This change has been 
      linked with an osteogenic phenotypic response. Statins have recently been shown 
      to have anti-inflammatory properties. We therefore hypothesized that statins may 
      have an anti-inflammatory effect on human AVICs by downregulation of 
      TLR4-stimulated inflammatory responses. Our purposes were (1) to determine the 
      effect of simvastatin on TLR4-induced expression of inflammatory mediators in 
      human AVICs and (2) to determine the mechanism(s) through which simvastatin exert 
      this effect. MATERIALS AND METHODS: Human AVICs were isolated from the explanted 
      hearts of four patients undergoing cardiac transplantation. Cells were treated 
      with simvastatin (50 muM) for 1 h before stimulation with TLR4 agonist 
      lipopolysaccharide (LPS, 0.2 mug/mL). Immunoblotting (IB) was used to analyze cell 
      lysates for ICAM-1 expression, and enzyme-linked immunosorbent assay was used to 
      detect IL-8 and MCP-1 in cell culture media. Likewise, lysates were analyzed for 
      TLR4 and nuclear factor-kappa B activation (IB). After simvastatin treatment, 
      lysates were analyzed for TLR4 levels (IB). Statistics were by analysis of 
      variance (P < 0.05). RESULTS: Simvastatin reduced TLR4-induced ICAM-1, IL-8, and 
      MCP-1 expression in AVICs. Simvastatin down-regulated TLR4 levels and suppressed 
      TLR4-induced phosphorylation of nuclear factor-kappa B. CONCLUSIONS: These data 
      demonstrate the potential of a medical therapy (simvastatin) to impact the 
      pathogenesis of aortic stenosis.
CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
FAU - Venardos, Neil
AU  - Venardos N
AD  - The Department of Surgery, Division of Cardiothoracic Surgery, University of 
      Colorado School of Medicine, Aurora, Colorado. Electronic address: 
      neil.venardos@ucdenver.edu.
FAU - Deng, Xin-Sheng
AU  - Deng XS
AD  - The Department of Surgery, Division of Cardiothoracic Surgery, University of 
      Colorado School of Medicine, Aurora, Colorado.
FAU - Yao, Quinzhou
AU  - Yao Q
AD  - The Department of Surgery, Division of Cardiothoracic Surgery, University of 
      Colorado School of Medicine, Aurora, Colorado.
FAU - Weyant, Michael J
AU  - Weyant MJ
AD  - The Department of Surgery, Division of Cardiothoracic Surgery, University of 
      Colorado School of Medicine, Aurora, Colorado.
FAU - Reece, T Brett
AU  - Reece TB
AD  - The Department of Surgery, Division of Cardiothoracic Surgery, University of 
      Colorado School of Medicine, Aurora, Colorado.
FAU - Meng, Xianzhong
AU  - Meng X
AD  - The Department of Surgery, Division of Cardiothoracic Surgery, University of 
      Colorado School of Medicine, Aurora, Colorado.
FAU - Fullerton, David A
AU  - Fullerton DA
AD  - The Department of Surgery, Division of Cardiothoracic Surgery, University of 
      Colorado School of Medicine, Aurora, Colorado.
LA  - eng
GR  - R01 HL106582/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20180525
PL  - United States
TA  - J Surg Res
JT  - The Journal of surgical research
JID - 0376340
RN  - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
RN  - 0 (TLR4 protein, human)
RN  - 0 (Toll-Like Receptor 4)
RN  - AGG2FN16EV (Simvastatin)
RN  - Aortic Valve, Calcification of
SB  - IM
MH  - Adult
MH  - Aortic Valve/cytology/immunology/*pathology
MH  - Aortic Valve Stenosis/*drug therapy/immunology/pathology
MH  - Calcinosis/*drug therapy/immunology/pathology
MH  - Cardiomyopathy, Dilated/surgery
MH  - Cells, Cultured
MH  - Drug Evaluation, Preclinical
MH  - Heart Transplantation
MH  - Humans
MH  - Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology/therapeutic use
MH  - Male
MH  - Middle Aged
MH  - Myofibroblasts
MH  - Primary Cell Culture
MH  - Simvastatin/*pharmacology/therapeutic use
MH  - Toll-Like Receptor 4/*immunology
PMC - PMC6092033
MID - NIHMS968052
OTO - NOTNLM
OT  - Aortic stenosis
OT  - Statin
OT  - Valve interstitial cell
EDAT- 2018/08/14 06:00
MHDA- 2019/06/14 06:00
PMCR- 2019/10/01
CRDT- 2018/08/14 06:00
PHST- 2017/09/09 00:00 [received]
PHST- 2018/04/18 00:00 [revised]
PHST- 2018/04/24 00:00 [accepted]
PHST- 2018/08/14 06:00 [entrez]
PHST- 2018/08/14 06:00 [pubmed]
PHST- 2019/06/14 06:00 [medline]
PHST- 2019/10/01 00:00 [pmc-release]
AID - S0022-4804(18)30297-X [pii]
AID - 10.1016/j.jss.2018.04.054 [doi]
PST - ppublish
SO  - J Surg Res. 2018 Oct;230:101-109. doi: 10.1016/j.jss.2018.04.054. Epub 2018 May 
      25.