NFATc1-E2F1-LMCD1-Mediated IL-33 Expression by Thrombin Is Required for Injury-Induced Neointima Formation

Suresh Govatati, Prahalathan Pichavaram, Jagadeesh Janjanam, Baolin Zhang, Nikhlesh Singh, Arul M. Mani, James G. Traylor, A. Wayne Orr, Rao Gadiparthi

Research output: Contribution to journalArticle

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), Gαq/11 (Gα protein q/11), PLCβ3 (phospholipase Cβ3), 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.

Original languageEnglish (US)
Pages (from-to)1212-1226
Number of pages15
JournalArteriosclerosis, thrombosis, and vascular biology
Volume39
Issue number6
DOIs
StatePublished - Jun 1 2019

Fingerprint

E2F1 Transcription Factor
Neointima
Thrombin
Cysteine
Wounds and Injuries
Smooth Muscle Myocytes
Neutralizing Antibodies
Cell Movement
T Cell Transcription Factor 1
E2F Transcription Factors
PAR-1 Receptor
NFATC Transcription Factors
Thrombin Time
Protein Domains
Interleukin-33
Phospholipases
Growth
GTP-Binding Proteins
Atherosclerosis
Arteries

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

NFATc1-E2F1-LMCD1-Mediated IL-33 Expression by Thrombin Is Required for Injury-Induced Neointima Formation. / Govatati, Suresh; Pichavaram, Prahalathan; Janjanam, Jagadeesh; Zhang, Baolin; Singh, Nikhlesh; Mani, Arul M.; Traylor, James G.; Orr, A. Wayne; Gadiparthi, Rao.

In: Arteriosclerosis, thrombosis, and vascular biology, Vol. 39, No. 6, 01.06.2019, p. 1212-1226.

Research output: Contribution to journalArticle

Govatati, Suresh ; Pichavaram, Prahalathan ; Janjanam, Jagadeesh ; Zhang, Baolin ; Singh, Nikhlesh ; Mani, Arul M. ; Traylor, James G. ; Orr, A. Wayne ; Gadiparthi, Rao. / NFATc1-E2F1-LMCD1-Mediated IL-33 Expression by Thrombin Is Required for Injury-Induced Neointima Formation. In: Arteriosclerosis, thrombosis, and vascular biology. 2019 ; Vol. 39, No. 6. pp. 1212-1226.
@article{2d56dff124f3416e87733edc47ae815a,
title = "NFATc1-E2F1-LMCD1-Mediated IL-33 Expression by Thrombin Is Required for Injury-Induced Neointima Formation",
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), Gαq/11 (Gα protein q/11), PLCβ3 (phospholipase Cβ3), 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.",
author = "Suresh Govatati and Prahalathan Pichavaram and Jagadeesh Janjanam and Baolin Zhang and Nikhlesh Singh and Mani, {Arul M.} and Traylor, {James G.} and Orr, {A. Wayne} and Rao Gadiparthi",
year = "2019",
month = "6",
day = "1",
doi = "10.1161/ATVBAHA.119.312729",
language = "English (US)",
volume = "39",
pages = "1212--1226",
journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",
issn = "1079-5642",
publisher = "Lippincott Williams and Wilkins",
number = "6",

}

TY - JOUR

T1 - NFATc1-E2F1-LMCD1-Mediated IL-33 Expression by Thrombin Is Required for Injury-Induced Neointima Formation

AU - Govatati, Suresh

AU - Pichavaram, Prahalathan

AU - Janjanam, Jagadeesh

AU - Zhang, Baolin

AU - Singh, Nikhlesh

AU - Mani, Arul M.

AU - Traylor, James G.

AU - Orr, A. Wayne

AU - Gadiparthi, Rao

PY - 2019/6/1

Y1 - 2019/6/1

N2 - 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), Gαq/11 (Gα protein q/11), PLCβ3 (phospholipase Cβ3), 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.

AB - 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), Gαq/11 (Gα protein q/11), PLCβ3 (phospholipase Cβ3), 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.

UR - http://www.scopus.com/inward/record.url?scp=85066512595&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85066512595&partnerID=8YFLogxK

U2 - 10.1161/ATVBAHA.119.312729

DO - 10.1161/ATVBAHA.119.312729

M3 - Article

VL - 39

SP - 1212

EP - 1226

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

SN - 1079-5642

IS - 6

ER -