Role of Excessive Autophagy Induced by Mechanical Overload in Vein Graft Neointima Formation: Prediction and Prevention

Chang, Ya Ju; Hsueh, Yuan Yu; Wang, Shao Wei; Su, Fong-Chin; Chang, Chih Han; Tang, Ming Jer; Li, Yi Shuan; Wang, Shyh-Hau; Shung, K. Kirk; Chien, Shu; Wu, Chia Ching

doi:10.1038/srep22147

Cited by 13 publications

(8 citation statements)

References 41 publications

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“…6). This is consistent with a recent finding showing that 3-MA prevented arterial restenosis [62]. The role of autophagy in PAH is interesting.…”

Section: Discussionsupporting

confidence: 93%

SUMOylation of Vps34 by SUMO1 promotes phenotypic switching of vascular smooth muscle cells by activating autophagy in pulmonary arterial hypertension

Yao

et al. 2019

Pulmonary Pharmacology & Therapeutics

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Introduction: Pulmonary arterial hypertension (PAH) is a life-threatening disease without effective therapies. PAH is associated with a progressive increase in pulmonary vascular resistance and irreversible pulmonary vascular remodeling. SUMO1 (small ubiquitin-related modifier 1) can bind to target proteins and lead to protein SUMOylation, an important post-translational modification with a key role in many diseases. However, the contribution of SUMO1 to PAH remains to be fully characterized. Methods: In this study, we explored the role of SUMO1 in the dedifferentiation of vascular smooth muscle cells (VSMCs) involved in hypoxia-induced pulmonary vascular remodeling and PAH in vivo and in vitro. Results: In a mouse model of hypoxic PAH, SUMO1 expression was significantly increased, which was associated with activation of autophagy (increased LC3b and decreased p62), dedifferentiation of pulmonary arterial VSMCs (reduced α-SMA, SM22 and SM-MHC), and pulmonary vascular remodeling. Similar results were obtained in a MCT-induced PAH model. Overexpression of SUMO1 significantly increased VSMCs proliferation, migration, hypoxia-induced VSMCs dedifferentiation, and autophagy, but these effects were abolished by inhibition of autophagy by 3-MA in aortic VSMCs. Furthermore, SUMO1 knockdown reversed hypoxia-induced proliferation and migration of PASMCs. Mechanistically, SUMO1 promotes Vps34 SUMOylation and the assembly of the Beclin-1-Vps34-Atg14 complex, thereby inducing autophagy, whereas Vps34 mutation K840R reduces Vps34 SUMOylation and inhibits VSMCs dedifferentiation. Discussion: Our data uncovers an important role of SUMO1 in VSMCs proliferation, migration, autophagy, and phenotypic switching (dedifferentiation) involved in pulmonary vascular remodeling and PAH. Targeting of the SUMO1-Vps34-autophagy signaling axis may be exploited to develop therapeutic strategies to treat PAH.

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“…6). This is consistent with a recent finding showing that 3-MA prevented arterial restenosis [62]. The role of autophagy in PAH is interesting.…”

Section: Discussionsupporting

confidence: 93%

SUMOylation of Vps34 by SUMO1 promotes phenotypic switching of vascular smooth muscle cells by activating autophagy in pulmonary arterial hypertension

Yao

et al. 2019

Pulmonary Pharmacology & Therapeutics

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“…The importance of mechanical factors on MSC differentiation was summarized in a recent review [ 57 ]. LSS, a mechanical force on the straight part of vascular endothelium, has vasoprotective function, suppresses inflammatory response [ 58 ], and promotes differentiation and tube formation on EPCs [ 59 ]. However, the angiogenic potential and functions in early and late EPCs are divergent [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

Endothelial differentiation of bone marrow mesenchyme stem cells applicable to hypoxia and increased migration through Akt and NFκB signals

Liu

Tsai

et al. 2017

Stem Cell Res Ther

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BackgroundBone marrow mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) are used to repair hypoxic or ischemic tissue. However, the underlining mechanism of resistance in the hypoxic microenvironment and the efficacy of migration to the injured tissue are still unknown. The current study aims to understand the hypoxia resistance and migration ability of MSCs during differentiation toward endothelial lineages by biochemical and mechanical stimuli.MethodMSCs were harvested from the bone marrow of 6–8-week-old Sprague–Dawley rats. The endothelial growth medium (EGM) was added to MSCs for 3 days to initiate endothelial differentiation. Laminar shear stress was used as the fluid mechanical stimulation.ResultsApplication of EGM facilitated the early endothelial lineage cells (eELCs) to express EPC markers. When treating the hypoxic mimetic desferrioxamine, both MSCs and eELCs showed resistance to hypoxia as compared with the occurrence of apoptosis in rat fibroblasts. The eELCs under hypoxia increased the wound closure and C-X-C chemokine receptor type 4 (CXCR4) gene expression. Although the shear stress promoted eELC maturation and aligned cells parallel to the flow direction, their migration ability was not superior to that of eELCs either under normoxia or hypoxia. The eELCs showed higher protein expressions of CXCR4, phosphorylated Akt (pAkt), and endogenous NFκB and IκBα than MSCs under both normoxia and hypoxia conditions. The potential migratory signals were discovered by inhibiting either Akt or NFκB using specific inhibitors and revealed decreases of wound closure and transmigration ability in eELCs.ConclusionThe Akt and NFκB pathways are important to regulate the early endothelial differentiation and its migratory ability under a hypoxic microenvironment.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0470-0) contains supplementary material, which is available to authorized users.

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“…For example, mechanical stress (strain, compression, shear stress, etc.) that induces autophagy 20 , 21 , compression forces that rapidly increases autophagosome numbers in cells 22 , and arteriovenous shear stress that causes excessive vascular endothelial cells autophagy and apoptosis 23 . Despite these findings, the role of intramedullary pressure (IMP) in autophagy after SCI is not known.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic effects of rapamycin and surgical decompression in a rabbit spinal cord injury model

et al. 2020

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Surgical decompression after spinal cord injury (SCI) is a conventional treatment. Although it has been proven to have clinical effects, there are certain limitations, such as the surgical conditions that must be met and the invasive nature of the treatment. Therefore, there is an urgent need to develop a simple and maneuverable therapy for the emergency treatment of patients with SCI before surgery. Rapamycin (RAPA) has been reported to have potential as a therapeutic agent for SCI. In this study, we observed the therapeutic effects of rapamycin and surgical decompression, in combination or separately, on the histopathology in rabbits with SCI. After combination therapy, intramedullary pressure (IMP) decreased significantly, autophagic flux increased, and apoptosis and demyelination were significantly reduced. Compared with RAPA/surgical decompression alone, the combination therapy had a significantly better effect. In addition, we evaluated the effects of mechanical pressure on autophagy after SCI by assessing changes in autophagic initiation, degradation, and flux. Increased IMP after SCI inhibited autophagic degradation and impaired autophagic flux. Decompression improved autophagic flux after SCI. Our findings provide novel evidence of a promising strategy for the treatment of SCI in the future. The combination therapy may effectively improve emergency treatment after SCI and promote the therapeutic effect of decompression. This study also contributes to a better understanding of the effects of mechanical pressure on autophagy after neurotrauma.

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Role of Excessive Autophagy Induced by Mechanical Overload in Vein Graft Neointima Formation: Prediction and Prevention

Cited by 13 publications

References 41 publications

SUMOylation of Vps34 by SUMO1 promotes phenotypic switching of vascular smooth muscle cells by activating autophagy in pulmonary arterial hypertension

SUMOylation of Vps34 by SUMO1 promotes phenotypic switching of vascular smooth muscle cells by activating autophagy in pulmonary arterial hypertension

Endothelial differentiation of bone marrow mesenchyme stem cells applicable to hypoxia and increased migration through Akt and NFκB signals

Therapeutic effects of rapamycin and surgical decompression in a rabbit spinal cord injury model

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