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

Cardiovascular Medicine

Mae K. Borchrdt¹  Shengyu Li¹  Khanh Chau¹  Priyanka Banerjee¹  Nhat-Tu Le¹  Estefani Berrios Turcios¹  Loka reddy Velatooru¹  Elizabeth A. Olmsted-Davis¹  Guangyu Wang¹  Rei J. Abe¹  John P. Cooke¹  Minh T. H. Nguyen²  Ling-Ling Lee³  Steven H. Lin³  Masaki Imanishi³  Keigi Fujiwara³  Jun-ichi Abe³  Venkata S. K. Samanthapudi³  Kyung Ae Ko³  Nicolas L. Palaskas³  Sivareddy Kotla³  Elena McBeath³  Young J. Gi³  Anita Deswal³  Robert Dantzer⁴ 

[1] Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States;Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States;Department of Life Science, Vietnam Academy of Science and Technology, University of Science and Technology of Hanoi, Hanoi, Vietnam;Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States;Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States;

关键词: atherosclerosis;    endothelial activation;    laminar flow;    CHK1;    SENP2;    SUMOylation;    fibrotic changes;   

DOI  :  10.3389/fcvm.2023.1187490

 received in 2023-03-21, accepted in 2023-07-24,  发布年份 2023

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

Unknown   
© 2023 Nguyen, Imanishi, Li, Chau, Banerjee, Velatooru, Ko, Samanthapudi, Lee, Abe, McBeath, Deswal, Lin, Palaskas, Dantzer, Fujiwara, Borchrdt, Turcios, Olmsted-Davis, Kotla, Cooke, Wang, Abe and Le.