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

Autor:	Nguyen MTH; 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., Imanishi M; Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Li S; Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States., Chau K; Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States., Banerjee P; Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States., Velatooru LR; Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States., Ko KA; Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Samanthapudi VSK; Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Gi YJ; Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Lee LL; Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Abe RJ; Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States., McBeath E; Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Deswal A; Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Lin SH; Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Palaskas NL; Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Dantzer R; Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Fujiwara K; Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Borchrdt MK; Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States., Turcios EB; Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States., Olmsted-Davis EA; Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States., Kotla S; Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Cooke JP; Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States., Wang G; Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States., Abe JI; Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Le NT; Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in cardiovascular medicine [Front Cardiovasc Med] 2023 Aug 30; Vol. 10, pp. 1187490. Date of Electronic Publication: 2023 Aug 30 (Print Publication: 2023).
DOI:	10.3389/fcvm.2023.1187490
Abstrakt:	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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (© 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.)
Databáze:	MEDLINE
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