De-SUMOylation enzyme of sentrin/SUMO-specific protease 2 regulates disturbed flow-induced SUMOylation of ERK5 and p53 that leads to endothelial dysfunction and atherosclerosis

Kyung-Sun Heo; Eugene Chang; Nhat-Tu Le; Hannah Cushman; Edward T H Yeh; Keigi Fujiwara; Jun-ichi Abe

doi:10.1161/CIRCRESAHA.111.300179

De-SUMOylation enzyme of sentrin/SUMO-specific protease 2 regulates disturbed flow-induced SUMOylation of ERK5 and p53 that leads to endothelial dysfunction and atherosclerosis

Kyung-Sun Heo, Eugene Chang, Nhat-Tu Le, Hannah Cushman, Edward T H Yeh, Keigi Fujiwara, Jun-ichi Abe

Research output: Contribution to journal › Article › peer-review

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Abstract

RATIONALE: Disturbed flow induces proinflammatory and apoptotic responses in endothelial cells, causing them to become dysfunctional and subsequently proatherogenic.

OBJECTIVE: Although a possible link between SUMOylation of p53 and ERK5 detected during endothelial apoptosis and inflammation has been suggested, the mechanistic insights, especially under the proatherogenic flow condition, remain largely unknown.

METHODS AND RESULTS: SUMOylation of p53 and ERK5 was induced by disturbed flow but not by steady laminar flow. To examine the role of the disturbed flow-induced p53 and ERK5 SUMOylation, we used de-SUMOylation enzyme of sentrin/Small Ubiquitin-like MOdifier (SUMO)-specific protease 2 deficiency (Senp2(+/-)) mice and observed a significant increase in endothelial apoptosis and adhesion molecule expression both in vitro and in vivo. These increases, however, were significantly inhibited in endothelial cells overexpressing p53 and ERK5 SUMOylation site mutants. Senp2(+/-) mice exhibited increased leukocyte rolling along the endothelium, and accelerated formation of atherosclerotic lesions was observed in Senp2(+/-)/Ldlr(-/-), but not in Senp2(+/+)/Ldlr(-/-), mice fed a high-cholesterol diet. Notably, the extent of lesion size in the aortic arch of Senp2(+/-)/Ldlr(-/-) mice was much larger than that in the descending aorta, also suggesting a crucial role of the disturbed flow-induced SUMOylation of proteins, including p53 and ERK5 in atherosclerosis formation.

CONCLUSIONS: These data show the unique role of sentrin/SUMO-specific protease 2 on endothelial function under disturbed flow and suggest that SUMOylation of p53 and ERK5 by disturbed flow contributes to the atherosclerotic plaque formation. Molecules involved in this newly discovered signaling will be useful targets for controlling endothelial cells dysfunction and consequently atherosclerosis formation.

Original language	English (US)
Pages (from-to)	911-23
Number of pages	13
Journal	Circulation Research
Volume	112
Issue number	6
DOIs	https://doi.org/10.1161/CIRCRESAHA.111.300179
State	Published - Mar 15 2013

Keywords

Animals
Apoptosis
Atherosclerosis
Bone Marrow Transplantation
Cell Adhesion Molecules
Down-Regulation
E-Selectin
Endothelial Cells
Endothelium, Vascular
Female
Hemorheology
Humans
Kruppel-Like Transcription Factors
Mice
Mice, Inbred C57BL
Mitogen-Activated Protein Kinase 7
Nitric Oxide Synthase Type III
Protein Processing, Post-Translational
SUMO-1 Protein
Small Ubiquitin-Related Modifier Proteins
Tumor Suppressor Protein p53
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

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10.1161/CIRCRESAHA.111.300179

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@article{8678497ea8704b0fad9d06961fb595e9,

title = "De-SUMOylation enzyme of sentrin/SUMO-specific protease 2 regulates disturbed flow-induced SUMOylation of ERK5 and p53 that leads to endothelial dysfunction and atherosclerosis",

abstract = "RATIONALE: Disturbed flow induces proinflammatory and apoptotic responses in endothelial cells, causing them to become dysfunctional and subsequently proatherogenic.OBJECTIVE: Although a possible link between SUMOylation of p53 and ERK5 detected during endothelial apoptosis and inflammation has been suggested, the mechanistic insights, especially under the proatherogenic flow condition, remain largely unknown.METHODS AND RESULTS: SUMOylation of p53 and ERK5 was induced by disturbed flow but not by steady laminar flow. To examine the role of the disturbed flow-induced p53 and ERK5 SUMOylation, we used de-SUMOylation enzyme of sentrin/Small Ubiquitin-like MOdifier (SUMO)-specific protease 2 deficiency (Senp2(+/-)) mice and observed a significant increase in endothelial apoptosis and adhesion molecule expression both in vitro and in vivo. These increases, however, were significantly inhibited in endothelial cells overexpressing p53 and ERK5 SUMOylation site mutants. Senp2(+/-) mice exhibited increased leukocyte rolling along the endothelium, and accelerated formation of atherosclerotic lesions was observed in Senp2(+/-)/Ldlr(-/-), but not in Senp2(+/+)/Ldlr(-/-), mice fed a high-cholesterol diet. Notably, the extent of lesion size in the aortic arch of Senp2(+/-)/Ldlr(-/-) mice was much larger than that in the descending aorta, also suggesting a crucial role of the disturbed flow-induced SUMOylation of proteins, including p53 and ERK5 in atherosclerosis formation.CONCLUSIONS: These data show the unique role of sentrin/SUMO-specific protease 2 on endothelial function under disturbed flow and suggest that SUMOylation of p53 and ERK5 by disturbed flow contributes to the atherosclerotic plaque formation. Molecules involved in this newly discovered signaling will be useful targets for controlling endothelial cells dysfunction and consequently atherosclerosis formation.",

keywords = "Animals, Apoptosis, Atherosclerosis, Bone Marrow Transplantation, Cell Adhesion Molecules, Down-Regulation, E-Selectin, Endothelial Cells, Endothelium, Vascular, Female, Hemorheology, Humans, Kruppel-Like Transcription Factors, Mice, Mice, Inbred C57BL, Mitogen-Activated Protein Kinase 7, Nitric Oxide Synthase Type III, Protein Processing, Post-Translational, SUMO-1 Protein, Small Ubiquitin-Related Modifier Proteins, Tumor Suppressor Protein p53, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't",

author = "Kyung-Sun Heo and Eugene Chang and Nhat-Tu Le and Hannah Cushman and Yeh, {Edward T H} and Keigi Fujiwara and Jun-ichi Abe",

year = "2013",

month = mar,

day = "15",

doi = "10.1161/CIRCRESAHA.111.300179",

language = "English (US)",

volume = "112",

pages = "911--23",

journal = "Circulation Research",

issn = "0009-7330",

publisher = "Lippincott Williams and Wilkins",

number = "6",

}

TY - JOUR

T1 - De-SUMOylation enzyme of sentrin/SUMO-specific protease 2 regulates disturbed flow-induced SUMOylation of ERK5 and p53 that leads to endothelial dysfunction and atherosclerosis

AU - Heo, Kyung-Sun

AU - Chang, Eugene

AU - Le, Nhat-Tu

AU - Cushman, Hannah

AU - Yeh, Edward T H

AU - Fujiwara, Keigi

AU - Abe, Jun-ichi

PY - 2013/3/15

Y1 - 2013/3/15

N2 - RATIONALE: Disturbed flow induces proinflammatory and apoptotic responses in endothelial cells, causing them to become dysfunctional and subsequently proatherogenic.OBJECTIVE: Although a possible link between SUMOylation of p53 and ERK5 detected during endothelial apoptosis and inflammation has been suggested, the mechanistic insights, especially under the proatherogenic flow condition, remain largely unknown.METHODS AND RESULTS: SUMOylation of p53 and ERK5 was induced by disturbed flow but not by steady laminar flow. To examine the role of the disturbed flow-induced p53 and ERK5 SUMOylation, we used de-SUMOylation enzyme of sentrin/Small Ubiquitin-like MOdifier (SUMO)-specific protease 2 deficiency (Senp2(+/-)) mice and observed a significant increase in endothelial apoptosis and adhesion molecule expression both in vitro and in vivo. These increases, however, were significantly inhibited in endothelial cells overexpressing p53 and ERK5 SUMOylation site mutants. Senp2(+/-) mice exhibited increased leukocyte rolling along the endothelium, and accelerated formation of atherosclerotic lesions was observed in Senp2(+/-)/Ldlr(-/-), but not in Senp2(+/+)/Ldlr(-/-), mice fed a high-cholesterol diet. Notably, the extent of lesion size in the aortic arch of Senp2(+/-)/Ldlr(-/-) mice was much larger than that in the descending aorta, also suggesting a crucial role of the disturbed flow-induced SUMOylation of proteins, including p53 and ERK5 in atherosclerosis formation.CONCLUSIONS: These data show the unique role of sentrin/SUMO-specific protease 2 on endothelial function under disturbed flow and suggest that SUMOylation of p53 and ERK5 by disturbed flow contributes to the atherosclerotic plaque formation. Molecules involved in this newly discovered signaling will be useful targets for controlling endothelial cells dysfunction and consequently atherosclerosis formation.

AB - RATIONALE: Disturbed flow induces proinflammatory and apoptotic responses in endothelial cells, causing them to become dysfunctional and subsequently proatherogenic.OBJECTIVE: Although a possible link between SUMOylation of p53 and ERK5 detected during endothelial apoptosis and inflammation has been suggested, the mechanistic insights, especially under the proatherogenic flow condition, remain largely unknown.METHODS AND RESULTS: SUMOylation of p53 and ERK5 was induced by disturbed flow but not by steady laminar flow. To examine the role of the disturbed flow-induced p53 and ERK5 SUMOylation, we used de-SUMOylation enzyme of sentrin/Small Ubiquitin-like MOdifier (SUMO)-specific protease 2 deficiency (Senp2(+/-)) mice and observed a significant increase in endothelial apoptosis and adhesion molecule expression both in vitro and in vivo. These increases, however, were significantly inhibited in endothelial cells overexpressing p53 and ERK5 SUMOylation site mutants. Senp2(+/-) mice exhibited increased leukocyte rolling along the endothelium, and accelerated formation of atherosclerotic lesions was observed in Senp2(+/-)/Ldlr(-/-), but not in Senp2(+/+)/Ldlr(-/-), mice fed a high-cholesterol diet. Notably, the extent of lesion size in the aortic arch of Senp2(+/-)/Ldlr(-/-) mice was much larger than that in the descending aorta, also suggesting a crucial role of the disturbed flow-induced SUMOylation of proteins, including p53 and ERK5 in atherosclerosis formation.CONCLUSIONS: These data show the unique role of sentrin/SUMO-specific protease 2 on endothelial function under disturbed flow and suggest that SUMOylation of p53 and ERK5 by disturbed flow contributes to the atherosclerotic plaque formation. Molecules involved in this newly discovered signaling will be useful targets for controlling endothelial cells dysfunction and consequently atherosclerosis formation.

KW - Animals

KW - Apoptosis

KW - Atherosclerosis

KW - Bone Marrow Transplantation

KW - Cell Adhesion Molecules

KW - Down-Regulation

KW - E-Selectin

KW - Endothelial Cells

KW - Endothelium, Vascular

KW - Female

KW - Hemorheology

KW - Humans

KW - Kruppel-Like Transcription Factors

KW - Mice

KW - Mice, Inbred C57BL

KW - Mitogen-Activated Protein Kinase 7

KW - Nitric Oxide Synthase Type III

KW - Protein Processing, Post-Translational

KW - SUMO-1 Protein

KW - Small Ubiquitin-Related Modifier Proteins

KW - Tumor Suppressor Protein p53

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1161/CIRCRESAHA.111.300179

DO - 10.1161/CIRCRESAHA.111.300179

M3 - Article

C2 - 23381569

SN - 0009-7330

VL - 112

SP - 911

EP - 923

JO - Circulation Research

JF - Circulation Research

IS - 6

ER -

De-SUMOylation enzyme of sentrin/SUMO-specific protease 2 regulates disturbed flow-induced SUMOylation of ERK5 and p53 that leads to endothelial dysfunction and atherosclerosis

Abstract

Keywords

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