TLR4 Stimulation Promotes Human AVIC Fibrogenic Activity through Upregulation of Neurotrophin 3 Production
Background: Calcific aortic valve disease (CAVD) is a chronic inflammatory disease that manifests as progressive valvular fibrosis and calcification. An inflammatory milieu in valvular tissue promotes fibrosis and calcification. Aortic valve interstitial cell (AVIC) proliferation and the over-produc...
Main Authors: | , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2020-02-01
|
Series: | International Journal of Molecular Sciences |
Subjects: | |
Online Access: | https://www.mdpi.com/1422-0067/21/4/1276 |
id |
doaj-56604f275eb04f17a9829b97aa823c24 |
---|---|
record_format |
Article |
spelling |
doaj-56604f275eb04f17a9829b97aa823c242020-11-25T01:40:01ZengMDPI AGInternational Journal of Molecular Sciences1422-00672020-02-01214127610.3390/ijms21041276ijms21041276TLR4 Stimulation Promotes Human AVIC Fibrogenic Activity through Upregulation of Neurotrophin 3 ProductionQingzhou Yao0Erlinda The1Lihua Ao2Yufeng Zhai3Maren K. Osterholt4David A. Fullerton5Xianzhong Meng6Department of Surgery, University of Colorado Denver, Box C-320, 12700 E 19th Avenue, Aurora, CO 80045, USADepartment of Surgery, University of Colorado Denver, Box C-320, 12700 E 19th Avenue, Aurora, CO 80045, USADepartment of Surgery, University of Colorado Denver, Box C-320, 12700 E 19th Avenue, Aurora, CO 80045, USADepartment of Surgery, University of Colorado Denver, Box C-320, 12700 E 19th Avenue, Aurora, CO 80045, USADepartment of Surgery, University of Colorado Denver, Box C-320, 12700 E 19th Avenue, Aurora, CO 80045, USADepartment of Surgery, University of Colorado Denver, Box C-320, 12700 E 19th Avenue, Aurora, CO 80045, USADepartment of Surgery, University of Colorado Denver, Box C-320, 12700 E 19th Avenue, Aurora, CO 80045, USABackground: Calcific aortic valve disease (CAVD) is a chronic inflammatory disease that manifests as progressive valvular fibrosis and calcification. An inflammatory milieu in valvular tissue promotes fibrosis and calcification. Aortic valve interstitial cell (AVIC) proliferation and the over-production of the extracellular matrix (ECM) proteins contribute to valvular thickening. However, the mechanism underlying elevated AVIC fibrogenic activity remains unclear. Recently, we observed that AVICs from diseased aortic valves express higher levels of neurotrophin 3 (NT3) and that NT3 exerts pro-osteogenic and pro-fibrogenic effects on human AVICs. Hypothesis: Pro-inflammatory stimuli upregulate NT3 production in AVICs to promote fibrogenic activity in human aortic valves. Methods and Results: AVICs were isolated from normal human aortic valves and were treated with lipopolysaccharide (LPS, 0.20 µg/mL). LPS induced TLR4-dependent NT3 production. This effect of LPS was abolished by inhibition of the Akt and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) pathways. The stimulation of TLR4 in human AVICs with LPS resulted in a greater proliferation rate and an upregulated production of matrix metallopeptidases-9 (MMP-9) and collagen III, as well as augmented collagen deposition. Recombinant NT3 promoted AVIC proliferation in a tropomyosin receptor kinase (Trk)-dependent fashion. The neutralization of NT3 or the inhibition of Trk suppressed LPS-induced AVIC fibrogenic activity. Conclusions: The stimulation of TLR4 in human AVICs upregulates NT3 expression and promotes cell proliferation and collagen deposition. The NT3-Trk cascade plays a critical role in the TLR4-mediated elevation of fibrogenic activity in human AVICs. Upregulated NT3 production by endogenous TLR4 activators may contribute to aortic valve fibrosis associated with CAVD progression.https://www.mdpi.com/1422-0067/21/4/1276tlr4neurotrophin 3fibrosisproliferationlps |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Qingzhou Yao Erlinda The Lihua Ao Yufeng Zhai Maren K. Osterholt David A. Fullerton Xianzhong Meng |
spellingShingle |
Qingzhou Yao Erlinda The Lihua Ao Yufeng Zhai Maren K. Osterholt David A. Fullerton Xianzhong Meng TLR4 Stimulation Promotes Human AVIC Fibrogenic Activity through Upregulation of Neurotrophin 3 Production International Journal of Molecular Sciences tlr4 neurotrophin 3 fibrosis proliferation lps |
author_facet |
Qingzhou Yao Erlinda The Lihua Ao Yufeng Zhai Maren K. Osterholt David A. Fullerton Xianzhong Meng |
author_sort |
Qingzhou Yao |
title |
TLR4 Stimulation Promotes Human AVIC Fibrogenic Activity through Upregulation of Neurotrophin 3 Production |
title_short |
TLR4 Stimulation Promotes Human AVIC Fibrogenic Activity through Upregulation of Neurotrophin 3 Production |
title_full |
TLR4 Stimulation Promotes Human AVIC Fibrogenic Activity through Upregulation of Neurotrophin 3 Production |
title_fullStr |
TLR4 Stimulation Promotes Human AVIC Fibrogenic Activity through Upregulation of Neurotrophin 3 Production |
title_full_unstemmed |
TLR4 Stimulation Promotes Human AVIC Fibrogenic Activity through Upregulation of Neurotrophin 3 Production |
title_sort |
tlr4 stimulation promotes human avic fibrogenic activity through upregulation of neurotrophin 3 production |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2020-02-01 |
description |
Background: Calcific aortic valve disease (CAVD) is a chronic inflammatory disease that manifests as progressive valvular fibrosis and calcification. An inflammatory milieu in valvular tissue promotes fibrosis and calcification. Aortic valve interstitial cell (AVIC) proliferation and the over-production of the extracellular matrix (ECM) proteins contribute to valvular thickening. However, the mechanism underlying elevated AVIC fibrogenic activity remains unclear. Recently, we observed that AVICs from diseased aortic valves express higher levels of neurotrophin 3 (NT3) and that NT3 exerts pro-osteogenic and pro-fibrogenic effects on human AVICs. Hypothesis: Pro-inflammatory stimuli upregulate NT3 production in AVICs to promote fibrogenic activity in human aortic valves. Methods and Results: AVICs were isolated from normal human aortic valves and were treated with lipopolysaccharide (LPS, 0.20 µg/mL). LPS induced TLR4-dependent NT3 production. This effect of LPS was abolished by inhibition of the Akt and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) pathways. The stimulation of TLR4 in human AVICs with LPS resulted in a greater proliferation rate and an upregulated production of matrix metallopeptidases-9 (MMP-9) and collagen III, as well as augmented collagen deposition. Recombinant NT3 promoted AVIC proliferation in a tropomyosin receptor kinase (Trk)-dependent fashion. The neutralization of NT3 or the inhibition of Trk suppressed LPS-induced AVIC fibrogenic activity. Conclusions: The stimulation of TLR4 in human AVICs upregulates NT3 expression and promotes cell proliferation and collagen deposition. The NT3-Trk cascade plays a critical role in the TLR4-mediated elevation of fibrogenic activity in human AVICs. Upregulated NT3 production by endogenous TLR4 activators may contribute to aortic valve fibrosis associated with CAVD progression. |
topic |
tlr4 neurotrophin 3 fibrosis proliferation lps |
url |
https://www.mdpi.com/1422-0067/21/4/1276 |
work_keys_str_mv |
AT qingzhouyao tlr4stimulationpromoteshumanavicfibrogenicactivitythroughupregulationofneurotrophin3production AT erlindathe tlr4stimulationpromoteshumanavicfibrogenicactivitythroughupregulationofneurotrophin3production AT lihuaao tlr4stimulationpromoteshumanavicfibrogenicactivitythroughupregulationofneurotrophin3production AT yufengzhai tlr4stimulationpromoteshumanavicfibrogenicactivitythroughupregulationofneurotrophin3production AT marenkosterholt tlr4stimulationpromoteshumanavicfibrogenicactivitythroughupregulationofneurotrophin3production AT davidafullerton tlr4stimulationpromoteshumanavicfibrogenicactivitythroughupregulationofneurotrophin3production AT xianzhongmeng tlr4stimulationpromoteshumanavicfibrogenicactivitythroughupregulationofneurotrophin3production |
_version_ |
1725047627425251328 |