ID | 119175 |
Author |
Nguyen, Minh T. H.
Houston Methodist Research Institute|University of Science and Technology of Hanoi
Imanishi, Masaki
The University of Texas MD Anderson Cancer Center
Tokushima University Educator and Researcher Directory
Li, Shengyu
Houston Methodist Research Institute
Chau, Khanh
Houston Methodist Research Institute
Banerjee, Priyanka
Houston Methodist Research Institute
Velatooru, Loka reddy
Houston Methodist Research Institute
Ko, Kyung Ae
The University of Texas MD Anderson Cancer Center
Samanthapudi, Venkata S. K.
The University of Texas MD Anderson Cancer Center
Gi, Young J.
The University of Texas MD Anderson Cancer Center
Lee, Ling-Ling
The University of Texas MD Anderson Cancer Center
Abe, Rei J.
Houston Methodist Research Institute
McBeath, Elena
The University of Texas MD Anderson Cancer Center
Deswal, Anita
The University of Texas MD Anderson Cancer Center
Lin, Steven H.
The University of Texas MD Anderson Cancer Center
Palaskas, Nicolas L.
The University of Texas MD Anderson Cancer Center
Dantzer, Robert
The University of Texas MD Anderson Cancer Center
Fujiwara, Keigi
The University of Texas MD Anderson Cancer Center
Borchrdt, Mae K.
Houston Methodist Research Institute
Turcios, Estefani Berrios
Houston Methodist Research Institute
Olmsted-Davis, Elizabeth A.
Houston Methodist Research Institute
Kotla, Sivareddy
The University of Texas MD Anderson Cancer Center
Cooke, John P.
Houston Methodist Research Institute
Wang, Guangyu
Houston Methodist Research Institute
Abe, Jun-ichi
The University of Texas MD Anderson Cancer Center
Le, Nhat-Tu
Houston Methodist Research Institute
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Keywords | atherosclerosis
endothelial activation
laminar flow
CHK1
SENP2
SUMOylation
fibrotic changes
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Content Type |
Journal Article
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Description | 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. |
Journal Title |
Frontiers in Cardiovascular Medicine
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ISSN | 2297055X
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Publisher | Frontiers Media S.A.
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Volume | 10
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Start Page | 1187490
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Published Date | 2023-08-30
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Rights | This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (https://creativecommons.org/licenses/by/4.0/). 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.
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language |
eng
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departments |
University Hospital
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