Notch1 signalling regulates endothelial proliferation and apoptosis in pulmonary arterial hypertension

Dabral, Swati; Tian, Xiaoling; Kojonazarov, Baktybek; Savai, Rajkumar; Ghofrani, Hossein Ardeschir; Weißmann, Norbert; Florio, Mónica; Sun, J. R.; Jonigk, Danny; Maegel, Lavinia; Grimminger, Friedrich; Seeger, Werner; Schermuly, Ralph Theo

doi:10.1183/13993003.00773-2015

Cited by 97 publications

(95 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In agreement with this hypothesis, TNF␣-induced apoptosis was increased by DAPT treatment, which under our experimental conditions inhibits Notch1 but not Notch2 or Notch4 activation, and it was reduced instead by overexpression of N1ICD. Whereas the role of Notch1 in protecting endothelial cells from apoptosis has been reported in the context of ischemia (42), disturbed shear stress (25), and in the endothelium of subjects with pulmonary hypertension (43), this is the first report showing the involvement of Notch1 in endothelial cell survival under the effect of an inflammatory cytokine.…”

Section: Estrogen Protection Of Endothelium Requires Notch1 Activationmentioning

confidence: 80%

Estrogen receptor β–dependent Notch1 activation protects vascular endothelium against tumor necrosis factor α (TNFα)-induced apoptosis

Fortini¹,

Sega²,

Caliceti

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

Unlike age-matched men, premenopausal women benefit from cardiovascular protection. Estrogens protect against apoptosis of endothelial cells (ECs), one of the hallmarks of endothelial dysfunction leading to cardiovascular disorders, but the underlying molecular mechanisms remain poorly understood. The inflammatory cytokine TNFα causes EC apoptosis while dysregulating the Notch pathway, a major contributor to EC survival. We have previously reported that 17β-estradiol (E2) treatment activates Notch signaling in ECs. Here, we sought to assess whether in TNFα-induced inflammation Notch is involved in E2-mediated protection of the endothelium. We treated human umbilical vein endothelial cells (HUVECs) with E2, TNFα, or both and found that E2 counteracts TNFα-induced apoptosis. When Notch1 was inhibited, this E2-mediated protection was not observed, whereas ectopic overexpression of Notch1 diminished TNFα-induced apoptosis. Moreover, TNFα reduced the levels of active Notch1 protein, which were partially restored by E2 treatment. Moreover, siRNA-mediated knockdown of estrogen receptor β (ERβ), but not ERα, abolished the effect of E2 on apoptosis. Additionally, the E2-mediated regulation of the levels of active Notch1 was abrogated after silencing ERβ. In summary, our results indicate that E2 requires active Notch1 through a mechanism involving ERβ to protect the endothelium in TNFα-induced inflammation. These findings could be relevant for assessing the efficacy and applicability of menopausal hormone treatment, because they may indicate that in women with impaired Notch signaling, hormone therapy might not effectively protect the endothelium.

show abstract

Section: Estrogen Protection Of Endothelium Requires Notch1 Activationmentioning

confidence: 80%

Estrogen receptor β–dependent Notch1 activation protects vascular endothelium against tumor necrosis factor α (TNFα)-induced apoptosis

Fortini¹,

Sega²,

Caliceti

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…As a downstream target of Notch, Survivin regulates both physiological and pathological process. Notch1 inhibited apoptosis of human pulmonary arterial endothelial cell (hPAECs) via downregulation of Survivin and Bcl-2 and increased proliferation via p21 [52]. During breast oncogenesis, HER2 stabilizes Survivin while concomitantly down-regulating Survivin gene transcription by suppressing Notch1 cleavage [53].…”

Section: Discussionmentioning

confidence: 99%

ASIC1 promotes differentiation of neuroblastoma by negatively regulating Notch signaling pathway

Liu¹,

Inoue

Leng

et al. 2016

Oncotarget

View full text Add to dashboard Cite

In neurons, up-regulation of Notch activity either inhibits neurite extension or causes retraction of neurites. Conversely, inhibition of Notch1 facilitates neurite extension. Acid-sensing ion channels (ASICs) are a family of proton-gated cation channels, which play critical roles in synaptic plasticity, learning and memory and spine morphogenesis. Our pilot proteomics data from ASIC1a knock out mice implicated that ASIC1a may play a role in regulating Notch signaling, therefore, we explored whether or not ASIC1a regulates neurite growth during neuronal development through Notch signaling. In this study, we determined the effects of ASIC1a on neurite growth in a mouse neuroblastoma cell line, NS20Y cells, by modulating ASIC1a expression. We also determined the relationship between ASIC1a and Notch signaling on neuronal differentiation. Our results showed that down-regulation of ASIC1a in NS20Y cells inhibits CPT-cAMP induced neurite growth, while over expression of ASIC1a promotes its growth. In addition, down-regulation of ASIC1a increased the expression of Notch1 and its target gene Survivin while inhibitor of Notch significantly prevented the neurite extension induced by ASIC1a in NS20Y cells. These data indicate that Notch1 signaling may be required for ASIC1a-mediated neurite growth and neuronal differentiation.

show abstract

“…Concurrently, the mammalian target of rapamycin (mTOR), a key regulator in diverse cellular functions, including protein synthesis and apoptosis, inhibited the cellular catabolic pathway, such as negatively regulated autophagy. (28) Previous study showed that mTOR repressed the autophagy in PAH (29) . Li et al (12) also indicated that mTOR ameliorated hypoxia-triggered PAH by autophagypathway.…”

Section: Discussionmentioning

confidence: 95%

β-Arrestins1 inhibit autophagy induced by hypoxic injury in human pulmonary artery endothelial cells via Akt/mTOR signaling pathway

Ning

Deng

Kong

et al. 2020

Preprint

View full text Add to dashboard Cite

Background To investigate the potential effects of β-Arrestins1 on autophagy and apoptosis in human pulmonary artery endothelial cells (hPAECs) under hypoxic stress. Methods The hPAECs were exposed to normoxic condition and hypoxic injury for 24 h, 48 h, and 72 h, respectively. Then, to explore effects of autophagy on hPAECs with hypoxia, cells were administrated with 3-MA (an inhibitor autophagy). β-Arrestins1 was regulated to explore its effects on autophagy and apoptosis of hPAECs. Transwell cell migration assay and scratch assay were performed to detect the migration by light microscope. Then, CCK-8 assay was used to investigate the proliferation of hPAECs. Meanwhile, TUNEL assay served as apoptosis in hPAECs. In addition, Western blotting assay applied to evaluate protein expressions. Results Hypoxia contributed to hyperproliferation, migration apoptosis resistance of hPAECs. Meanwhile, autophagy was increased in hypoxic hPAECs. Excessive proliferation、migration and apoptosis resistance of hPAECs were reversed after inhibition of autophagy. Then, the β-Arrestins1 and VEGFR3 expression levels were decreased in hypoxic conditions. Moreover, the activity of Akt/mTOR signal pathway was restrained after hypoxic injury. At last, β-Arrestins1+/+ repressed the increased autophagy and apoptosis resistance of hPAECs under hypoxia. Conclusions Our study indicated that β-Arrestins1 mediated VEGFR3 reduced excessive autophagy and apoptosis resistance via Akt/mTOR pathway of hPAECs under hypoxia. It may provide a promising therapeutic target for pulmonary artery hypertension (PAH).

show abstract

Notch1 signalling regulates endothelial proliferation and apoptosis in pulmonary arterial hypertension

Cited by 97 publications

References 43 publications

Estrogen receptor β–dependent Notch1 activation protects vascular endothelium against tumor necrosis factor α (TNFα)-induced apoptosis

Estrogen receptor β–dependent Notch1 activation protects vascular endothelium against tumor necrosis factor α (TNFα)-induced apoptosis

ASIC1 promotes differentiation of neuroblastoma by negatively regulating Notch signaling pathway

β-Arrestins1 inhibit autophagy induced by hypoxic injury in human pulmonary artery endothelial cells via Akt/mTOR signaling pathway

Contact Info

Product

Resources

About