Differential expression of Hedgehog/Notch and transforming growth factor-β in human abdominal aortic aneurysms

Doyle, Adam J.; Redmond, Eileen M.; Gillespie, David L.; Knight, Peter A.; Cullen, John P.; Cahill, Paul A.; Morrow, David

doi:10.1016/j.jvs.2014.02.053

Cited by 33 publications

(26 citation statements)

References 28 publications

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“…Inhibition of Wnt16 by TGFβ represses Notch signaling, permitting the TGFβ-induced chondrogenic transformation program in VSMCs. A similar correlation between activated TGFβ and attenuated Notch signaling was described in de-differentiating VSMCs of the aneurysmal aortic wall 40 indicating a potentially broad involvement of TGFβ-Notch antagonism in vascular pathologies. We detected a similar reduction in Notch receptors, ligands and target In both MGP-null aortae and in TGFβ-treated VSMCs.…”

Section: Discussionsupporting

confidence: 64%

Wnt16 Attenuates TGFβ-Induced Chondrogenic Transformation in Vascular Smooth Muscle

Beazley

Nurminsky

Lima

et al. 2015

ATVB

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Objective Phenotypic plasticity of vascular smooth muscle cells (VSMCs) contributes to cardiovascular disease. Chondrocyte-like transformation of VSMCs associates with vascular calcification and underlies the formation of aortic cartilaginous metaplasia induced in mice by genetic loss of matrix Gla protein (MGP). Previous microarray analysis identified a dramatic down-regulation of Wnt16 in calcified MGP-null aortae, suggesting an antagonistic role for Wnt16 in the chondrogenic transformation of VSMCs. Approach and Results Wnt16 is significantly down-regulated in MGP-null aortae, before the histological appearance of cartilaginous metaplasia, and in primary MGP-null VSMCs. In contrast, intrinsic TGFβ is activated in MGP-null VSMCs and is necessary for spontaneous chondrogenesis of these cells in high-density micromass cultures. TGFβ3-induced chondrogenic transformation in wild-type VSMCs associates with Smad2/3-dependent Wnt16 down-regulation, but Wnt16 does not suppress TGFβ3-induced Smad activation. In addition, TGFβ3 inhibits Notch signaling in wild-type VSMCs and this pathway is down-regulated in MGP-null aortae. Exogenous Wnt16 stimulates Notch activity and attenuates TGFβ3-induced down-regulation of Notch in wild-type VSMCs, prevents chondrogenesis in MGP-null and TGFβ3-treated wild-type VSMCs, and stabilizes expression of contractile markers of differentiated VMSCs. Conclusions We describe a novel TGFβ-Wnt16-Notch signaling conduit in the chondrocyte-like transformation of VSMCs and identify endogenous TGFβ activity in MGP-null VSMCs as a critical mediator of chondrogenesis. Our proposed model suggests that the activated TGFβ pathway inhibits expression of Wnt16 which is a positive regulator of Notch signaling and a stabilizer of VSMC phenotype. These data advance the comprehensive mechanistic understanding of VSMC transformation and may identify a novel potential therapeutic target in vascular calcification.

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Section: Discussionsupporting

confidence: 64%

Wnt16 Attenuates TGFβ-Induced Chondrogenic Transformation in Vascular Smooth Muscle

Beazley

Nurminsky

Lima

et al. 2015

ATVB

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“…Hh signaling promotes proliferation of monociliated choroid plexus tumor cells in a Notch-dependent pathway [21]. Inactivating Hh results in decreased expression of the Hh/Notch signaling component [20]. Inhibiting the Hh pathway suppresses Notch signaling and induces a mesenchymal-to-epithelial-like transition [19].…”

Section: Discussionmentioning

confidence: 99%

GANT61, a GLI inhibitor, sensitizes glioma cells to the temozolomide treatment

Cai

Zhao

et al. 2016

J Exp Clin Cancer Res

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BackgroundThe aim of this study was to investigate the effect of downregulating Hedgehog pathway by GANT61 on human glioma cells, examine the consequent changes of temozolomide (TMZ)-induced effects and explore the molecular mechanisms.MethodsThe cytotoxicity of a Gli1/2 inhibitor, GANT61 was examined both alone and in combination with TMZ in human glioma cell lines. The mRNA and protein expression alterations were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot, respectively. CCK-8 assay detected the cell proliferative capability. Apoptotic cell number was measured by flow cytometry. The transwell assay was used to test the cell invasive capability. DNA damage effect was identified by COMET assay and γH2AX expression.ResultsProliferation of tumor cells treated with GANT61 in combination with TMZ was significantly suppressed compared with those treated with either drug used alone. The combination treatment induced a higher rate of apoptosis, DNA damage and reduced the invasive capability of glioma cells. DNA damage repair enzyme MGMT and the Notch1 pathway increased in the cells treated by TMZ treatment. However, GANT61 could abrogated the protein increasing.ConclusionsGANT61 sensitizes glioma cells to TMZ treatment by enhancing DNA damage effect, decreasing MGMT expression and the Notch1 pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0463-3) contains supplementary material, which is available to authorized users.

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“…Although it has been most extensively studied in thoracic aortic aneurysms, TGF-β may also have a mechanistic role in AAAs [31]. Systemic blockade of TGF-β activity or genetic deletion of SMAD3, a downstream signal of TGF-β, augmented AngII and calcium chloride-induced AAAs [32,33].…”

Section: Pathological Mechanisms Of Aaa Developmentmentioning

confidence: 99%

Abdominal aortic aneurysm

Davis

Rateri

Daugherty

2015

Current Opinion in Cardiology

133

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Purpose of review Abdominal aortic aneurysm (AAA) is a pathological condition of permanent dilation that portends the potentially fatal consequence of aortic rupture. This review emphasizes recent advances in mechanistic insight into aneurysm pathogenesis and potential pharmacologic therapies that are on the horizon for AAAs. Recent Findings An increasing body of evidence demonstrates that genetic factors, including 3p12.3, DAB2IP, LDLr, LRP1, MMP3, TGFβR2 and SORT1 loci, are associated with AAA development. Current human studies and animal models have shown that many leukocytes and inflammatory mediators, such as IL-1, IL-17, TGF-β and angiotensin II, are involved in the pathogenesis of AAAs. Leukocytic infiltration into aortic media leads to smooth muscle cell depletion, generation of reactive oxygen species, and extracellular matrix fragmentation. Recent preclinical investigations into pharmacological therapies for AAAs have provided intriguing insight for roles of microRNAs to regulate many pathological pathways in AAA development. Several large clinical trials are ongoing seeking to translate preclinical findings into therapeutic options. Summary Recent studies have identified many potential mechanisms involved in AAA pathogenesis that provide insight for the development of a medical treatment for this disease.

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Differential expression of Hedgehog/Notch and transforming growth factor-β in human abdominal aortic aneurysms

Cited by 33 publications

References 28 publications

Wnt16 Attenuates TGFβ-Induced Chondrogenic Transformation in Vascular Smooth Muscle

Wnt16 Attenuates TGFβ-Induced Chondrogenic Transformation in Vascular Smooth Muscle

GANT61, a GLI inhibitor, sensitizes glioma cells to the temozolomide treatment

Abdominal aortic aneurysm

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