Soluble Jagged-1 Inhibits Neointima Formation by Attenuating Notch-Herp2 Signaling

Caolo, Vincenza; Schulten, Henny; Zhuang, Zhen W.; Murakami, Masahiro; Wagenaar, Allard; Verbruggen, Sanne; Molin, Daniël; Post, Mark J.

doi:10.1161/atvbaha.110.217935

Cited by 39 publications

(31 citation statements)

References 37 publications

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“…30 It also has been reported that expression of soluble Jagged1 interferes with Notch signaling and can reduce the neointima formation induced by balloon injury. 31 The present results indicate that CKD plays a role in Notch-induced responses, because it increases the expression of the Notch receptors in AVFs and the expression of the Notch target gene, Hes1, in AVFs ( Figure 3B). Our results provide the first evidence for a mechanism by which CKD activates Notch signaling in AVFs, especially in the endothelium (Figure 3).…”

Section: Discussionsupporting

confidence: 51%

Blocking Notch in Endothelial Cells Prevents Arteriovenous Fistula Failure Despite CKD

Wang

Liang

Luo

et al. 2014

Journal of the American Society of Nephrology

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Neointima formation causes the failure of 60% of arteriovenous fistulas (AVFs) within 2 years. Neointimaforming mechanisms are controversial but possibly linked to excess proinflammatory responses and dysregulated Notch signaling. To identify how AVFs fail, we anastomosed the carotid artery to the internal jugular vein in normal and uremic mice and compared these findings with those in failed AVFs from patients with ESRD. Endothelial cells (ECs) of AVFs in uremic mice or patients expressed mesenchymal markers (FSP-1 and/or a-SMA) and exhibited increased expression and nuclear localization of Notch intracellular domain compared with ECs of AVFs in pair-fed control mice. Furthermore, expression of VE-Cadherin decreased, whereas expression of Notch1 and -4, Notch ligands, the downstream transcription factor of Notch, RBP-Jk, and Notch target genes increased in ECs of AVFs in uremic mice. In cultured ECs, ectopic expression of Notch ligand or treatment with TGF-b1 triggered the expression of mesenchymal markers and induced endothelial cell barrier dysfunction, both of which were blocked by Notch inhibition or RBP-Jk knockout. Furthermore, Notch-induced defects in barrier function, invasion of inflammatory cells, and neointima formation were suppressed in mice with heterozygous knockdown of endothelial-specific RBP-Jk. These results suggest that increased TGF-b1, a complication of uremia, activates Notch in endothelial cells of AVFs, leading to accelerated neointima formation and AVF failure. Suppression of Notch activation could be a strategy for improving AFV function in uremia.

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Section: Discussionsupporting

confidence: 51%

Blocking Notch in Endothelial Cells Prevents Arteriovenous Fistula Failure Despite CKD

Wang

Liang

Luo

et al. 2014

Journal of the American Society of Nephrology

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“…This finding may be significant because of a recent study that Ad-sJag1 infection in vitro reduced Herp2 mRNA expression in vSMCs, suggesting an inhibitory effect on Notch/Jagged1 signaling. 26 From in vitro and in vivo studies, it has been demonstrated that Herp2, as downstream of the Notch/Jagged1 signaling, regulates vSMCs differentiation and migration, and induces vascular remodeling in response to stimuli.10,27 Furthermore, the observation that the hampered proliferation of the Ad-sJag-treated vSMCs could be partially rescued by Herp2 overexpression suggests that Notch-Herp2 signaling is required for vSMCs function, and that sJag1 is an inhibitor for notch signaling both in vivo and in vitro. …”

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confidence: 99%

Soluble Jagged1 Inhibits Pulmonary Hypertension by Attenuating Notch Signaling

Xiao

Gong

Wang

2013

ATVB

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Objective-Notch signaling has been implicated in the development of pulmonary arterial hypertension (PH) as reflected by increased expression of Notch member proteins that induce the proliferation of pulmonary arterial smooth muscle cells (PASMCs). Soluble Jagged1 (sJag1) has been shown to inhibit Notch signaling in vitro and in vivo; however, its capacity to suppress PH remains unknown. Approach and Results-Notch1, Notch3, Jagged1, and Herp2 protein were highly expressed in both the mouse model of hypoxia-induced PH and the rat model of monocrotaline-induced PH. By attenuation and reversal of multiple pathological processes that were associated with PH, adenoviral sJag1 transfection significantly reduced the proliferation and enhanced the apoptosis of PASMCs in PH, whereas vehicle had no effect. The sJag1 inhibitory effect on Notch activation is likely related to its interference with ligand-induced signaling. Importantly, the administration with adenoviral sJag1 improved the survival rate of PH rats. Furthermore, sJag1 can restore the PH-PASMCs phenotype from the dedifferentiated to the differentiated state, by giving a positive effect on the physical binding of myocardin to the CC(A/T) n GG (CArG)-containing regions of vascular smooth muscle cells-specific promoters. Conclusions-Our results demonstrated that the potential therapeutic use of the sJag1 may not only inhibit the proliferation of PASMCs but also restore the PH-PASMCs phenotype from the dedifferentiated to the differentiated state through interference with Notch-Herp2 signaling. Because proliferation of PASMCs is a prerequisite for all kinds of PH, we hypothesized that blockage of Notch signaling could inhibit formation and development of PH. Soluble Jagged1 (sJag1) has been shown to inhibit Notch signaling in vitro and in vivo 16,17 ; however, its capacity to suppress PH remains unknown. Here, we showed that 2 kinds of rodent PH models, including the hypoxia-induced mouse and the monocrotaline (MCT)-induced rat, were inhibited by administration of sJag1 treatment. Accordingly, sJag1 was able to reduce the PASMCs proliferation and restore the phenotype by interfering with Notch signaling involving depression of Herp2 expression. Materials and MethodsMaterials and Methods are available in the online-only Supplement. Results Notch/Jagged1 Signaling Was Highly Activated in PHTo investigate the expression pattern of Notch signaling pathway in normal and PH lungs, we studied 2 kinds of PH rodent models including hypoxia-induced mouse and MTC-induced rat. The Verhoeff-Van Gieson stain sections for lung tissue clearly showed that there was significantly increased vascular medial thickening in the PH models of rat ( Figure 1A) and mouse. Consistent with this observation, our studies showed that the mean pulmonary arterial pressures (mPAP) by day 35 in hypoxia-mouse and by day 42 in MTC-rat were significantly higher than those in normal ( Figure 2B). Collectively, it was suggested that PH has been successfully induced in the hypoxia-treated mouse and MTC-tr...

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“…S2C), IL1␤ treatment could liberate E-boxes of the AC8 promoter to allow the NF-B-dependent transcription of this gene, because IL1␤/ NF-B pathways are known to be involved in the inflammatory response of VSMC (10,11,37). Preventing NF-B activation by overexpressing a mutated nonphosphorylatable/nondegradable form of IB␣ (32)(33)(34)(35)(36), reverses the AC8 up-regulation mediated by IL1␤ (supplemental Fig. S5).…”

Section: Discussionmentioning

confidence: 99%

The Notch Pathway Attenuates Interleukin 1β (IL1β)-mediated Induction of Adenylyl Cyclase 8 (AC8) Expression during Vascular Smooth Muscle Cell (VSMC) Trans-differentiation

Keuylian¹,

Baaij²,

Glorian³

et al. 2012

Journal of Biological Chemistry

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Soluble Jagged-1 Inhibits Neointima Formation by Attenuating Notch-Herp2 Signaling

Cited by 39 publications

References 37 publications

Blocking Notch in Endothelial Cells Prevents Arteriovenous Fistula Failure Despite CKD

Blocking Notch in Endothelial Cells Prevents Arteriovenous Fistula Failure Despite CKD

Soluble Jagged1 Inhibits Pulmonary Hypertension by Attenuating Notch Signaling

The Notch Pathway Attenuates Interleukin 1β (IL1β)-mediated Induction of Adenylyl Cyclase 8 (AC8) Expression during Vascular Smooth Muscle Cell (VSMC) Trans-differentiation

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