Journal article
NFATc1-E2F1-LMCD1-Mediated IL-33 Expression by Thrombin Is Required for Injury-Induced Neointima Formation
Arteriosclerosis, thrombosis, and vascular biology, Vol.39(6), pp.1212-1226
06/01/2019
DOI: 10.1161/ATVBAHA.119.312729
PMCID: PMC6540998
PMID: 31043075
Abstract
Objective-IL (interleukin)-33 has been shown to play a role in endothelial dysfunction, but its role in atherosclerosis is controversial. Therefore, the purpose of this study is to examine its role in vascular wall remodeling following injury.
Approach and Results-Thrombin induced IL-33 expression in a time-dependent manner in human aortic smooth muscle cells and inhibition of its activity by its neutralizing antibody suppressed thrombin induced human aortic smooth muscle cell migration but not DNA synthesis. In exploring the mechanisms, we found that Par1 (protease-activated receptor 1), Gaq/11 (G alpha protein q/11), PLC beta 3 (phospholipase C beta 3), NFATc1 (nuclear factor of activated T cells), E2F1 (E2F transcription factor 1), and LMCD1 (LIM and cysteine-rich domains protein 1) are involved in thrombin-induced IL-33 expression and migration. Furthermore, we identified an NFAT-binding site at -100 nt that mediates thrombin-induced IL-33 promoter activity. Interestingly, we observed that NFATc1, E2F1, and LMCD1 bind to NFAT site in response to thrombin and found that LMCD1, while alone has no significant effect, enhanced either NFATc1 or E2F1-dependent IL-33 promoter activity. In addition, we found that guidewire injury induces IL-33 expression in SMC and its neutralizing antibodies substantially reduce SMC migration and neointimal growth in vivo. Increased expression of IL-33 was also observed in human atherosclerotic lesions as compared to arteries without any lesions.
Conclusions-The above findings reveal for the first time that thrombin-induced human aortic smooth muscle cell migration and injury-induced neointimal growth require IL-33 expression. In addition, thrombin-induced IL-33 expression requires LMCD1 enhanced combinatorial activation of NFATc1 and E2F1.
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Details
- Title: Subtitle
- NFATc1-E2F1-LMCD1-Mediated IL-33 Expression by Thrombin Is Required for Injury-Induced Neointima Formation
- Creators
- Suresh Govatati - University of Tennessee Health Science CenterPrahalathan Pichavaram - University of Tennessee Health Science CenterJagadeesh Janjanam - University of Tennessee Health Science CenterBaolin Zhang - University of Tennessee at KnoxvilleNikhlesh K. Singh - University of Tennessee Health Science CenterArul M. Mani - University of Tennessee Health Science CenterJames G. Traylor - Louisiana State University Health Sciences Center ShreveportA. Wayne Orr - Louisiana State University Health Sciences Center ShreveportGadiparthi N. Rao - University of Tennessee Health Science Center
- Resource Type
- Journal article
- Publication Details
- Arteriosclerosis, thrombosis, and vascular biology, Vol.39(6), pp.1212-1226
- DOI
- 10.1161/ATVBAHA.119.312729
- PMID
- 31043075
- PMCID
- PMC6540998
- NLM abbreviation
- Arterioscler Thromb Vasc Biol
- ISSN
- 1079-5642
- eISSN
- 1524-4636
- Publisher
- Lippincott Williams & Wilkins
- Number of pages
- 15
- Grant note
- HL069908 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01HL133497; R01HL098435; R01HL141155; R01HL069908 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) P20GM121307 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS)
- Language
- English
- Date published
- 06/01/2019
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984384323502771
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