| Item type |
文献 / Documents(1) |
| 公開日 |
2024-04-16 |
| アクセス権 |
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|
アクセス権 |
open access |
| 資源タイプ |
|
|
資源タイプ識別子 |
http://purl.org/coar/resource_type/c_6501 |
|
資源タイプ |
journal article |
| 出版社版DOI |
|
|
|
識別子タイプ |
DOI |
|
|
関連識別子 |
https://doi.org/10.3389/fcvm.2023.1187490 |
|
|
言語 |
ja |
|
|
関連名称 |
10.3389/fcvm.2023.1187490 |
| 出版タイプ |
|
|
出版タイプ |
VoR |
|
出版タイプResource |
http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| タイトル |
|
|
タイトル |
Endothelial activation and fibrotic changes are impeded by laminar flow-induced CHK1-SENP2 activity through mechanisms distinct from endothelial-to-mesenchymal cell transition |
|
言語 |
en |
| 著者 |
Nguyen, Minh T. H.
今西, 正樹
Li, Shengyu
Chau, Khanh
Banerjee, Priyanka
Velatooru, Loka reddy
Ko, Kyung Ae
Samanthapudi, Venkata S. K.
Gi, Young J.
Lee, Ling-Ling
アベ, レイ
McBeath, Elena
Deswal, Anita
Lin, Steven H.
Palaskas, Nicolas L.
Dantzer, Robert
フジワラ, ケイジ
Borchrdt, Mae K.
Turcios, Estefani Berrios
Olmsted-Davis, Elizabeth A.
Kotla, Sivareddy
Cooke, John P.
Wang, Guangyu
アベ, ジュンイチ
Le, Nhat-Tu
|
| 抄録 |
|
|
内容記述タイプ |
Abstract |
|
内容記述 |
Background: The deSUMOylase sentrin-specific isopeptidase 2 (SENP2) plays a crucial role in atheroprotection. However, the phosphorylation of SENP2 at T368 under disturbed flow (D-flow) conditions hinders its nuclear function and promotes endothelial cell (EC) activation. SUMOylation has been implicated in D-flow-induced endothelial-to-mesenchymal transition (endoMT), but the precise role of SENP2 in counteracting this process remains unclear.
Method: We developed a phospho-specific SENP2 S344 antibody and generated knock-in (KI) mice with a phospho-site mutation of SENP2 S344A using CRISPR/Cas9 technology. We then investigated the effects of SENP2 S344 phosphorylation under two distinct flow patterns and during hypercholesteremia (HC)-mediated EC activation.
Result: Our findings demonstrate that laminar flow (L-flow) induces phosphorylation of SENP2 at S344 through the activation of checkpoint kinase 1 (CHK1), leading to the inhibition of ERK5 and p53 SUMOylation and subsequent suppression of EC activation. We observed a significant increase in lipid-laden lesions in both the aortic arch (under D-flow) and descending aorta (under L-flow) of female hypercholesterolemic SENP2 S344A KI mice. In male hypercholesterolemic SENP2 S344A KI mice, larger lipid-laden lesions were only observed in the aortic arch area, suggesting a weaker HC-mediated atherogenesis in male mice compared to females. Ionizing radiation (IR) reduced CHK1 expression and SENP2 S344 phosphorylation, attenuating the pro-atherosclerotic effects observed in female SENP2 S344A KI mice after bone marrow transplantation (BMT), particularly in L-flow areas. The phospho-site mutation SENP2 S344A upregulates processes associated with EC activation, including inflammation, migration, and proliferation. Additionally, fibrotic changes and up-regulated expression of EC marker genes were observed. Apoptosis was augmented in ECs derived from the lungs of SENP2 S344A KI mice, primarily through the inhibition of ERK5-mediated expression of DNA damage-induced apoptosis suppressor (DDIAS).
Summary: In this study, we have revealed a novel mechanism underlying the suppressive effects of L-flow on EC inflammation, migration, proliferation, apoptosis, and fibrotic changes through promoting CHK1-induced SENP2 S344 phosphorylation. The phospho-site mutation SENP2 S344A responds to L-flow through a distinct mechanism, which involves the upregulation of both mesenchymal and EC marker genes. |
|
言語 |
en |
| キーワード |
|
|
言語 |
en |
|
主題Scheme |
Other |
|
主題 |
atherosclerosis |
| キーワード |
|
|
言語 |
en |
|
主題Scheme |
Other |
|
主題 |
endothelial activation |
| キーワード |
|
|
言語 |
en |
|
主題Scheme |
Other |
|
主題 |
laminar flow |
| キーワード |
|
|
言語 |
en |
|
主題Scheme |
Other |
|
主題 |
CHK1 |
| キーワード |
|
|
言語 |
en |
|
主題Scheme |
Other |
|
主題 |
SENP2 |
| キーワード |
|
|
言語 |
en |
|
主題Scheme |
Other |
|
主題 |
SUMOylation |
| キーワード |
|
|
言語 |
en |
|
主題Scheme |
Other |
|
主題 |
fibrotic changes |
| 書誌情報 |
en : Frontiers in Cardiovascular Medicine
巻 10,
p. 1187490,
発行日 2023-08-30
|
| 収録物ID |
|
|
収録物識別子タイプ |
ISSN |
|
収録物識別子 |
2297055X |
| 出版者 |
|
|
出版者 |
Frontiers Media S.A. |
|
言語 |
en |
| 権利情報 |
|
|
言語 |
en |
|
権利情報 |
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
| EID |
|
|
識別子 |
406134 |
|
識別子タイプ |
URI |
| 言語 |
|
|
言語 |
eng |
fcvm_10_1187490.pdf (21.6 MB)
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