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Sesn2 attenuates the damage of endothelial progenitor cells induced by angiotensin II through regulating the Keap1/Nrf2 signal pathway.

ABSTRACT: Endothelial progenitor cell (EPC) dysfunction is an important physiopathological mechanism in the dynamics of the formation of atherosclerosis. It has been reported that angiotensin II (Ang-II) damages the function of EPCs in atherosclerotic plaque through induction of oxidative stress. Sestrin 2 (Sesn2) serves as an antioxidant role in oxidative stress, however, the exact mechanisms underlying the dynamics of how Sesn2 may factor into EPCs after Ang-II treatments needs to be illustrated. We isolated EPCs from human umbilical cord blood samples and treated with Ang-II. Western blotting, qRT-PCR, transwell assays, immunofluorescence and so on were used to investigate the mechanisms underlying the roles of Sesn2 in EPCs treated with Ang-II. Ang-II was found to promote the apoptosis of EPCs as well as inhibited the mRNA and protein expression of Sesn2. Upregulation of Sesn2 attenuated the negative effect of Ang-II. Sesn2 increased the protein expression of Nrf2 by enhancing P62-dependent autophagy. Silencing of Nrf2 enhanced the degree of apoptosis of EPCs as well as resulted in the impairment of EPC functions through inducing the promotion of (reactive oxygen species) ROS production. Our study results indicated that Sesn2 facilitated the viability of EPCs After treatment with Ang-II, as well as provided a potential therapeutic target to alleviate the progression of atherosclerosis.

SUBMITTER: Ding S

PROVIDER: S-EPMC7803511 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Sesn2 attenuates the damage of endothelial progenitor cells induced by angiotensin II through regulating the Keap1/Nrf2 signal pathway.

Ding Shiao S Ma Nan N Liu Hao H Tang Min M Mei Ju J

Aging 20201124 24

Endothelial progenitor cell (EPC) dysfunction is an important physiopathological mechanism in the dynamics of the formation of atherosclerosis. It has been reported that angiotensin II (Ang-II) damages the function of EPCs in atherosclerotic plaque through induction of oxidative stress. Sestrin 2 (Sesn2) serves as an antioxidant role in oxidative stress, however, the exact mechanisms underlying the dynamics of how Sesn2 may factor into EPCs after Ang-II treatments needs to be illustrated. We iso ...[more]

PMID: 33231566

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Project description:BackgroundNew vessel formation plays a pivotal role in the pathogenesis of neovascular-related diseases. Endothelial progenitor cells (EPCs) were found to contribute to neovascular-related diseases and interference with EPC neovascularization may be a novel target for these diseases. Zoledronate (Zol) was reported to exhibit anti-angiogenic effect. Basing on these evidences, we proposed that Zol may affect EPC function to exert novel anti-angiogenic effect. In this study, we therefore investigated the effects of Zol on multiple aspects of EPC function and explored the underlying mechanisms involved.Methodology/principal findingsEPCs were cultured from bone marrow derived mononuclear cells. The potential effects of Zol on Angiotensin II (Ang II)-stimulated EPC proliferation, migration, adhesion, in vitro tube formation were investigated. The results showed that Ang II (1 µM) enhanced EPC migration, adhesion, in vitro tube formation but had no effect on cell proliferation. Zol (75 and 100 µM) inhibited proliferation of EPCs and 50 µM geranylgeranyol (GGOH) could reverse the decrease of EPC proliferation. We found for the first time that Zol (50-100 µM) dose dependently attenuated migration, adhesion, and in vitro tube formation of EPCs stimulated by Ang II. GGOH could reverse the attenuation of EPC function induced by Zol. However, Zol did not induce EPC apoptosis. In addition, the underlying mechanisms were determined. The results revealed that Zol markedly down-regulated active RhoA stimulated by Ang II and inhibited the phosphorylation of Erk1/2 and JNK. Moreover, RhoA silencing resulted in a notable inhibition of EPC in vitro tube formation, suggesting that RhoA suppression played a pivotal role in Zol antiangiogenic effect.Conclusions/significanceThese findings suggested that Zol attenuated the promotion of EPC function stimulated by Ang II and exhibited novel antiangiogenic effect via RhoA and MAPK signaling. Thus, Zol may be served as a novel therapeutic agent for neovascular-related diseases treatment.

Dataset Information

Sesn2 attenuates the damage of endothelial progenitor cells induced by angiotensin II through regulating the Keap1/Nrf2 signal pathway.

Publications

Sesn2 attenuates the damage of endothelial progenitor cells induced by angiotensin II through regulating the Keap1/Nrf2 signal pathway.

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