Tumor necrosis factor-α regulates p27kip expression and apoptosis in smooth muscle cells of human carotid plaques via forkhead transcription factor O1

Guanghong Jia, Anshu Aggarwal, Steve H. Tyndall, Devendra K. Agrawal

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Apoptosis of vascular smooth muscle cells (SMCs) is controlled by a balance between the effect of growth factors and cytokines, and is involved in plaque instability in advanced atherosclerotic lesions. Recently, we reported high levels of atheroma-associated cytokines, including tumor necrosis factor-α (TNF-α), in carotid plaques of symptomatic patients. These cytokines induce apoptosis of vascular SMCs, and thus could be responsible for plaque rupture, a clinically devastating event. In this study, we examined the effect of TNF-α on the cell cycle inhibitor p27kip and apoptosis of SMCs in human carotid plaques, and the underlying mechanism. Both Forkhead box subclass o1 (FoxO1) and p27kip were more strongly expressed in symptomatic than asymptomatic atherosclerotic plaques. TNF-α significantly induced the expression of FoxO1 in asymptomatic plaque SMCs in a dose- and time-dependent manner via JNK signaling pathway. TNF-α also induced phosphorylation of FoxO1, resulting in its cytoplasmic translocation/nuclear exclusion of transcription factors. The effect of TNF-α was blocked by the PI3K inhibitor, LY294002. Meanwhile, TNF-α not only induced the p27kip expression and cell cycle arrest in the G0-G1 phase, but also enhanced caspase-3 activity and induced apoptosis in SMCs of asymptomatic plaques. However, the potential effect of TNF-α on the cell cycle inhibitor p27kip and apoptosis of SMCs was inhibited by siRNA against FoxO1 in asymptomatic patients. These data suggest the involvement of FoxO1 transcription factor in TNF-α-induced expression of a cell cycle regulatory protein and apoptosis of SMCs, thus regulating the stability of atherosclerotic plaques with carotid stenosis.

Original languageEnglish
Pages (from-to)1-8
Number of pages8
JournalExperimental and Molecular Pathology
Volume90
Issue number1
DOIs
StatePublished - Feb 2011

Fingerprint

Forkhead Transcription Factors
Smooth Muscle Myocytes
Muscle
Tumor Necrosis Factor-alpha
Cells
Apoptosis
Atherosclerotic Plaques
Cytokines
Vascular Smooth Muscle
Cell Cycle
Transcription Factors
Cell Cycle Resting Phase
Cell Cycle Proteins
Phosphorylation
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
MAP Kinase Signaling System
Carotid Stenosis
G1 Phase
Cell Cycle Checkpoints
Phosphatidylinositol 3-Kinases

All Science Journal Classification (ASJC) codes

  • Clinical Biochemistry
  • Molecular Biology
  • Pathology and Forensic Medicine

Cite this

Tumor necrosis factor-α regulates p27kip expression and apoptosis in smooth muscle cells of human carotid plaques via forkhead transcription factor O1. / Jia, Guanghong; Aggarwal, Anshu; Tyndall, Steve H.; Agrawal, Devendra K.

In: Experimental and Molecular Pathology, Vol. 90, No. 1, 02.2011, p. 1-8.

Research output: Contribution to journalArticle

@article{24a0988edf274f7cb750b5fea29c0cd2,
title = "Tumor necrosis factor-α regulates p27kip expression and apoptosis in smooth muscle cells of human carotid plaques via forkhead transcription factor O1",
abstract = "Apoptosis of vascular smooth muscle cells (SMCs) is controlled by a balance between the effect of growth factors and cytokines, and is involved in plaque instability in advanced atherosclerotic lesions. Recently, we reported high levels of atheroma-associated cytokines, including tumor necrosis factor-α (TNF-α), in carotid plaques of symptomatic patients. These cytokines induce apoptosis of vascular SMCs, and thus could be responsible for plaque rupture, a clinically devastating event. In this study, we examined the effect of TNF-α on the cell cycle inhibitor p27kip and apoptosis of SMCs in human carotid plaques, and the underlying mechanism. Both Forkhead box subclass o1 (FoxO1) and p27kip were more strongly expressed in symptomatic than asymptomatic atherosclerotic plaques. TNF-α significantly induced the expression of FoxO1 in asymptomatic plaque SMCs in a dose- and time-dependent manner via JNK signaling pathway. TNF-α also induced phosphorylation of FoxO1, resulting in its cytoplasmic translocation/nuclear exclusion of transcription factors. The effect of TNF-α was blocked by the PI3K inhibitor, LY294002. Meanwhile, TNF-α not only induced the p27kip expression and cell cycle arrest in the G0-G1 phase, but also enhanced caspase-3 activity and induced apoptosis in SMCs of asymptomatic plaques. However, the potential effect of TNF-α on the cell cycle inhibitor p27kip and apoptosis of SMCs was inhibited by siRNA against FoxO1 in asymptomatic patients. These data suggest the involvement of FoxO1 transcription factor in TNF-α-induced expression of a cell cycle regulatory protein and apoptosis of SMCs, thus regulating the stability of atherosclerotic plaques with carotid stenosis.",
author = "Guanghong Jia and Anshu Aggarwal and Tyndall, {Steve H.} and Agrawal, {Devendra K.}",
year = "2011",
month = "2",
doi = "10.1016/j.yexmp.2010.11.001",
language = "English",
volume = "90",
pages = "1--8",
journal = "Experimental and Molecular Pathology",
issn = "0014-4800",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - Tumor necrosis factor-α regulates p27kip expression and apoptosis in smooth muscle cells of human carotid plaques via forkhead transcription factor O1

AU - Jia, Guanghong

AU - Aggarwal, Anshu

AU - Tyndall, Steve H.

AU - Agrawal, Devendra K.

PY - 2011/2

Y1 - 2011/2

N2 - Apoptosis of vascular smooth muscle cells (SMCs) is controlled by a balance between the effect of growth factors and cytokines, and is involved in plaque instability in advanced atherosclerotic lesions. Recently, we reported high levels of atheroma-associated cytokines, including tumor necrosis factor-α (TNF-α), in carotid plaques of symptomatic patients. These cytokines induce apoptosis of vascular SMCs, and thus could be responsible for plaque rupture, a clinically devastating event. In this study, we examined the effect of TNF-α on the cell cycle inhibitor p27kip and apoptosis of SMCs in human carotid plaques, and the underlying mechanism. Both Forkhead box subclass o1 (FoxO1) and p27kip were more strongly expressed in symptomatic than asymptomatic atherosclerotic plaques. TNF-α significantly induced the expression of FoxO1 in asymptomatic plaque SMCs in a dose- and time-dependent manner via JNK signaling pathway. TNF-α also induced phosphorylation of FoxO1, resulting in its cytoplasmic translocation/nuclear exclusion of transcription factors. The effect of TNF-α was blocked by the PI3K inhibitor, LY294002. Meanwhile, TNF-α not only induced the p27kip expression and cell cycle arrest in the G0-G1 phase, but also enhanced caspase-3 activity and induced apoptosis in SMCs of asymptomatic plaques. However, the potential effect of TNF-α on the cell cycle inhibitor p27kip and apoptosis of SMCs was inhibited by siRNA against FoxO1 in asymptomatic patients. These data suggest the involvement of FoxO1 transcription factor in TNF-α-induced expression of a cell cycle regulatory protein and apoptosis of SMCs, thus regulating the stability of atherosclerotic plaques with carotid stenosis.

AB - Apoptosis of vascular smooth muscle cells (SMCs) is controlled by a balance between the effect of growth factors and cytokines, and is involved in plaque instability in advanced atherosclerotic lesions. Recently, we reported high levels of atheroma-associated cytokines, including tumor necrosis factor-α (TNF-α), in carotid plaques of symptomatic patients. These cytokines induce apoptosis of vascular SMCs, and thus could be responsible for plaque rupture, a clinically devastating event. In this study, we examined the effect of TNF-α on the cell cycle inhibitor p27kip and apoptosis of SMCs in human carotid plaques, and the underlying mechanism. Both Forkhead box subclass o1 (FoxO1) and p27kip were more strongly expressed in symptomatic than asymptomatic atherosclerotic plaques. TNF-α significantly induced the expression of FoxO1 in asymptomatic plaque SMCs in a dose- and time-dependent manner via JNK signaling pathway. TNF-α also induced phosphorylation of FoxO1, resulting in its cytoplasmic translocation/nuclear exclusion of transcription factors. The effect of TNF-α was blocked by the PI3K inhibitor, LY294002. Meanwhile, TNF-α not only induced the p27kip expression and cell cycle arrest in the G0-G1 phase, but also enhanced caspase-3 activity and induced apoptosis in SMCs of asymptomatic plaques. However, the potential effect of TNF-α on the cell cycle inhibitor p27kip and apoptosis of SMCs was inhibited by siRNA against FoxO1 in asymptomatic patients. These data suggest the involvement of FoxO1 transcription factor in TNF-α-induced expression of a cell cycle regulatory protein and apoptosis of SMCs, thus regulating the stability of atherosclerotic plaques with carotid stenosis.

UR - http://www.scopus.com/inward/record.url?scp=78649783839&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78649783839&partnerID=8YFLogxK

U2 - 10.1016/j.yexmp.2010.11.001

DO - 10.1016/j.yexmp.2010.11.001

M3 - Article

VL - 90

SP - 1

EP - 8

JO - Experimental and Molecular Pathology

JF - Experimental and Molecular Pathology

SN - 0014-4800

IS - 1

ER -