Endothelial activation and fibrotic changes are impeded by laminar flow-induced CHK1-SENP2 activity through mechanisms distinct from endothelial-to-mesenchymal cell transition
BackgroundThe 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 implicat...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-08-01
|
| Series: | Frontiers in Cardiovascular Medicine |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2023.1187490/full |
| _version_ | 1797730971414429696 |
|---|---|
| author | Minh T. H. Nguyen Minh T. H. Nguyen Masaki Imanishi Shengyu Li Khanh Chau Priyanka Banerjee Loka reddy Velatooru Kyung Ae Ko Venkata S. K. Samanthapudi Young J. Gi Ling-Ling Lee Rei J. Abe Elena McBeath Anita Deswal Steven H. Lin Nicolas L. Palaskas Robert Dantzer Keigi Fujiwara Mae K. Borchrdt Estefani Berrios Turcios Elizabeth A. Olmsted-Davis Sivareddy Kotla John P. Cooke Guangyu Wang Jun-ichi Abe Nhat-Tu Le |
| author_facet | Minh T. H. Nguyen Minh T. H. Nguyen Masaki Imanishi Shengyu Li Khanh Chau Priyanka Banerjee Loka reddy Velatooru Kyung Ae Ko Venkata S. K. Samanthapudi Young J. Gi Ling-Ling Lee Rei J. Abe Elena McBeath Anita Deswal Steven H. Lin Nicolas L. Palaskas Robert Dantzer Keigi Fujiwara Mae K. Borchrdt Estefani Berrios Turcios Elizabeth A. Olmsted-Davis Sivareddy Kotla John P. Cooke Guangyu Wang Jun-ichi Abe Nhat-Tu Le |
| author_sort | Minh T. H. Nguyen |
| collection | DOAJ |
| description | BackgroundThe 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.MethodWe 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.ResultOur 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).SummaryIn 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. |
| first_indexed | 2024-03-12T11:51:51Z |
| format | Article |
| id | doaj.art-b6f1e08e085d437dabddc7e3719fecfb |
| institution | Directory Open Access Journal |
| issn | 2297-055X |
| language | English |
| last_indexed | 2024-03-12T11:51:51Z |
| publishDate | 2023-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-b6f1e08e085d437dabddc7e3719fecfb2023-08-31T06:48:41ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2023-08-011010.3389/fcvm.2023.11874901187490Endothelial activation and fibrotic changes are impeded by laminar flow-induced CHK1-SENP2 activity through mechanisms distinct from endothelial-to-mesenchymal cell transitionMinh T. H. Nguyen0Minh T. H. Nguyen1Masaki Imanishi2Shengyu Li3Khanh Chau4Priyanka Banerjee5Loka reddy Velatooru6Kyung Ae Ko7Venkata S. K. Samanthapudi8Young J. Gi9Ling-Ling Lee10Rei J. Abe11Elena McBeath12Anita Deswal13Steven H. Lin14Nicolas L. Palaskas15Robert Dantzer16Keigi Fujiwara17Mae K. Borchrdt18Estefani Berrios Turcios19Elizabeth A. Olmsted-Davis20Sivareddy Kotla21John P. Cooke22Guangyu Wang23Jun-ichi Abe24Nhat-Tu Le25Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United StatesDepartment of Life Science, Vietnam Academy of Science and Technology, University of Science and Technology of Hanoi, Hanoi, VietnamDepartment of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesCenter for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United StatesCenter for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United StatesCenter for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United StatesCenter for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United StatesDepartment of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesCenter for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United StatesDepartment of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesCenter for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United StatesCenter for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United StatesCenter for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United StatesDepartment of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesCenter for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United StatesCenter for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United StatesDepartment of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesCenter for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United StatesBackgroundThe 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.MethodWe 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.ResultOur 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).SummaryIn 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.https://www.frontiersin.org/articles/10.3389/fcvm.2023.1187490/fullatherosclerosisendothelial activationlaminar flowCHK1SENP2SUMOylation |
| spellingShingle | Minh T. H. Nguyen Minh T. H. Nguyen Masaki Imanishi Shengyu Li Khanh Chau Priyanka Banerjee Loka reddy Velatooru Kyung Ae Ko Venkata S. K. Samanthapudi Young J. Gi Ling-Ling Lee Rei J. Abe Elena McBeath Anita Deswal Steven H. Lin Nicolas L. Palaskas Robert Dantzer Keigi Fujiwara Mae K. Borchrdt Estefani Berrios Turcios Elizabeth A. Olmsted-Davis Sivareddy Kotla John P. Cooke Guangyu Wang Jun-ichi Abe Nhat-Tu Le Endothelial activation and fibrotic changes are impeded by laminar flow-induced CHK1-SENP2 activity through mechanisms distinct from endothelial-to-mesenchymal cell transition Frontiers in Cardiovascular Medicine atherosclerosis endothelial activation laminar flow CHK1 SENP2 SUMOylation |
| title | Endothelial activation and fibrotic changes are impeded by laminar flow-induced CHK1-SENP2 activity through mechanisms distinct from endothelial-to-mesenchymal cell transition |
| title_full | Endothelial activation and fibrotic changes are impeded by laminar flow-induced CHK1-SENP2 activity through mechanisms distinct from endothelial-to-mesenchymal cell transition |
| title_fullStr | Endothelial activation and fibrotic changes are impeded by laminar flow-induced CHK1-SENP2 activity through mechanisms distinct from endothelial-to-mesenchymal cell transition |
| title_full_unstemmed | Endothelial activation and fibrotic changes are impeded by laminar flow-induced CHK1-SENP2 activity through mechanisms distinct from endothelial-to-mesenchymal cell transition |
| title_short | Endothelial activation and fibrotic changes are impeded by laminar flow-induced CHK1-SENP2 activity through mechanisms distinct from endothelial-to-mesenchymal cell transition |
| title_sort | endothelial activation and fibrotic changes are impeded by laminar flow induced chk1 senp2 activity through mechanisms distinct from endothelial to mesenchymal cell transition |
| topic | atherosclerosis endothelial activation laminar flow CHK1 SENP2 SUMOylation |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2023.1187490/full |
| work_keys_str_mv | AT minhthnguyen endothelialactivationandfibroticchangesareimpededbylaminarflowinducedchk1senp2activitythroughmechanismsdistinctfromendothelialtomesenchymalcelltransition AT minhthnguyen endothelialactivationandfibroticchangesareimpededbylaminarflowinducedchk1senp2activitythroughmechanismsdistinctfromendothelialtomesenchymalcelltransition AT masakiimanishi endothelialactivationandfibroticchangesareimpededbylaminarflowinducedchk1senp2activitythroughmechanismsdistinctfromendothelialtomesenchymalcelltransition AT shengyuli endothelialactivationandfibroticchangesareimpededbylaminarflowinducedchk1senp2activitythroughmechanismsdistinctfromendothelialtomesenchymalcelltransition AT khanhchau endothelialactivationandfibroticchangesareimpededbylaminarflowinducedchk1senp2activitythroughmechanismsdistinctfromendothelialtomesenchymalcelltransition AT priyankabanerjee endothelialactivationandfibroticchangesareimpededbylaminarflowinducedchk1senp2activitythroughmechanismsdistinctfromendothelialtomesenchymalcelltransition AT lokareddyvelatooru endothelialactivationandfibroticchangesareimpededbylaminarflowinducedchk1senp2activitythroughmechanismsdistinctfromendothelialtomesenchymalcelltransition AT kyungaeko endothelialactivationandfibroticchangesareimpededbylaminarflowinducedchk1senp2activitythroughmechanismsdistinctfromendothelialtomesenchymalcelltransition AT venkatasksamanthapudi endothelialactivationandfibroticchangesareimpededbylaminarflowinducedchk1senp2activitythroughmechanismsdistinctfromendothelialtomesenchymalcelltransition AT youngjgi endothelialactivationandfibroticchangesareimpededbylaminarflowinducedchk1senp2activitythroughmechanismsdistinctfromendothelialtomesenchymalcelltransition AT linglinglee endothelialactivationandfibroticchangesareimpededbylaminarflowinducedchk1senp2activitythroughmechanismsdistinctfromendothelialtomesenchymalcelltransition AT reijabe endothelialactivationandfibroticchangesareimpededbylaminarflowinducedchk1senp2activitythroughmechanismsdistinctfromendothelialtomesenchymalcelltransition AT elenamcbeath endothelialactivationandfibroticchangesareimpededbylaminarflowinducedchk1senp2activitythroughmechanismsdistinctfromendothelialtomesenchymalcelltransition AT anitadeswal endothelialactivationandfibroticchangesareimpededbylaminarflowinducedchk1senp2activitythroughmechanismsdistinctfromendothelialtomesenchymalcelltransition AT stevenhlin endothelialactivationandfibroticchangesareimpededbylaminarflowinducedchk1senp2activitythroughmechanismsdistinctfromendothelialtomesenchymalcelltransition AT nicolaslpalaskas endothelialactivationandfibroticchangesareimpededbylaminarflowinducedchk1senp2activitythroughmechanismsdistinctfromendothelialtomesenchymalcelltransition AT robertdantzer endothelialactivationandfibroticchangesareimpededbylaminarflowinducedchk1senp2activitythroughmechanismsdistinctfromendothelialtomesenchymalcelltransition AT keigifujiwara endothelialactivationandfibroticchangesareimpededbylaminarflowinducedchk1senp2activitythroughmechanismsdistinctfromendothelialtomesenchymalcelltransition AT maekborchrdt endothelialactivationandfibroticchangesareimpededbylaminarflowinducedchk1senp2activitythroughmechanismsdistinctfromendothelialtomesenchymalcelltransition AT estefaniberriosturcios endothelialactivationandfibroticchangesareimpededbylaminarflowinducedchk1senp2activitythroughmechanismsdistinctfromendothelialtomesenchymalcelltransition AT elizabethaolmsteddavis endothelialactivationandfibroticchangesareimpededbylaminarflowinducedchk1senp2activitythroughmechanismsdistinctfromendothelialtomesenchymalcelltransition AT sivareddykotla endothelialactivationandfibroticchangesareimpededbylaminarflowinducedchk1senp2activitythroughmechanismsdistinctfromendothelialtomesenchymalcelltransition AT johnpcooke endothelialactivationandfibroticchangesareimpededbylaminarflowinducedchk1senp2activitythroughmechanismsdistinctfromendothelialtomesenchymalcelltransition AT guangyuwang endothelialactivationandfibroticchangesareimpededbylaminarflowinducedchk1senp2activitythroughmechanismsdistinctfromendothelialtomesenchymalcelltransition AT junichiabe endothelialactivationandfibroticchangesareimpededbylaminarflowinducedchk1senp2activitythroughmechanismsdistinctfromendothelialtomesenchymalcelltransition AT nhattule endothelialactivationandfibroticchangesareimpededbylaminarflowinducedchk1senp2activitythroughmechanismsdistinctfromendothelialtomesenchymalcelltransition |