Endothelial activation and fibrotic changes are impeded by laminar flow-induced CHK1-SENP2 activity through mechanisms distinct from endothelial-to-mesenchymal cell transition

• Published in: Frontiers in cardiovascular medicine Vol. 10; p. 1187490
• Main Authors: Nguyen, Minh T H, Imanishi, Masaki, Li, Shengyu, Chau, Khanh, Banerjee, Priyanka, Velatooru, Loka Reddy, Ko, Kyung Ae, Samanthapudi, Venkata S K, Gi, Young J, Lee, Ling-Ling, Abe, Rei J, McBeath, Elena, Deswal, Anita, Lin, Steven H, Palaskas, Nicolas L, Dantzer, Robert, Fujiwara, Keigi, Borchrdt, Mae K, Turcios, Estefani Berrios, Olmsted-Davis, Elizabeth A, Kotla, Sivareddy, Cooke, John P, Wang, Guangyu, Abe, Jun-Ichi, Le, Nhat-Tu
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 30.08.2023
• Subjects: atherosclerosis; Cardiovascular Medicine; CHK1; endothelial activation; laminar flow; SENP2; SUMOylation; atherosclerosis; CHK1; fibrotic changes; laminar flow; SUMOylation; SENP2; endothelial activation
• ISSN: 2297-055X; 2297-055X
• DOI: 10.3389/fcvm.2023.1187490

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. 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. 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). 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.