DNA Enzyme ED5 Depletes Egr-1 and Inhibits Neointimal Hyperplasia in Rats

Wang, Tairan; Yang, Guang; Gui-nan, Liu

doi:10.1159/000350364

Cited by 7 publications

(5 citation statements)

References 77 publications

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“…Egr-1 belongs to the family of zinc finger transcription factors and plays an important role in vascular proliferative responses (16). Egr-1 governs the expression of several genes that play a deleterious role in vascular biology and has been implicated in intimal thickening in response to vascular injury and the development of atherosclerotic lesions (13,42). ET-1, as well as several growth factors and inflammatory cytokines, has been shown to induce its expression in several cell types including both endothelial cells and VSMCs (18,20,(43)(44)(45)(46).…”

Section: Discussionmentioning

confidence: 99%

“…The early growth response factor-1 (Egr-1) is a zinc finger transcription factor that regulates the transcription of several genes involved in cardiovascular functions (13,14). Egr-1 has been suggested to contribute to the progression of vascular disease processes, such as intimal thickening following vascular injury (15), atherosclerosis and cardiac hypertrophy (16,17).…”

Section: Introductionmentioning

confidence: 99%

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Src tyrosine kinase mediates endothelin-1-induced early growth response protein-1 expression via MAP kinase-dependent pathways in vascular smooth muscle cells

Simo‐Cheyou

Vardatsikos

Srivastava

2016

International Journal of Molecular Medicine

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We have previously demonstrated that the non-receptor protein tyrosine kinase (NR-PTK) c-Src is an upstream regulator of endothelin-1 (ET-1) and angiotensin II-induced activation of protein kinase B (PKB) signaling in vascular smooth muscle cells (VSMCs). We have also demonstrated that ET-1 potently induces the expression of the early growth response protein-1 (Egr-1), a zinc finger transcription factor that is overexpressed in models of vascular diseases, such as atherosclerosis. However, the involvement of c-Src in ET-1‑induced Egr-1 expression has not yet been investigated and its role in mitogen-activated protein kinase (MAPK) signaling remains controversial. Therefore, the aim of the present study was to examine the role of c-Src in the ET-1-induced phosphorylation of extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and p38 MAPK, 3 key members of the MAPK family and in the regulation of Egr-1 expression in rat aortic A10 VSMCs. ET-1 rapidly induced the phosphorylation of MAPKs, as well as the expression of Egr-1; however, treatment of the VSMCs with PP2, a specific pharmacological inhibitor of c-Src, dose-dependently reduced the phosphorylation of the 3 MAPKs and the expression of Egr-1 induced by ET-1. Furthermore, in mouse embryonic fibroblasts (MEFs) deficient in c-Src (SYF), the ET-1-induced Egr-1 expression and MAPK phosphorylation were significantly suppressed, as compared to MEFs expressing normal Src levels. These results suggest that c-Src plays a critical role in mediating ET-1-induced MAPK phosphorylation and Egr-1 expression in VSMCs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Src tyrosine kinase mediates endothelin-1-induced early growth response protein-1 expression via MAP kinase-dependent pathways in vascular smooth muscle cells

Simo‐Cheyou

Vardatsikos

Srivastava

2016

International Journal of Molecular Medicine

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“…ED5 inhibited vascular smooth muscle cell (SMC) growth and intimal thickening in balloon-injured rat carotid arteries, a finding later confirmed by Liu and colleagues who used ED5 to inhibit Egr-1 and TGFb expression, resulting in increased levels of nitric oxide synthase and NO and preservation of endothelial cell function (31). Wang and colleagues further found ED5 reduced levels of Egr-1 and platelet-derived growth factor (PDGF)-BB, cdk4, cyclin D1, monocyte chemotactic factor (MCP)-1, and intercellular adhesion molecule (ICAM)-1 (32). In a rat autologous vein graft model, Liu and colleagues used essentially the same DNAzyme (EDRz) to suppress Egr-1 expression, SMC proliferation, and intimal thickening (33).…”

Section: Dnazymes As Versatile Experimental Drugs In Noncancerous Setmentioning

confidence: 81%

“…DNAzymes have been evaluated in a wide range of experimental allograft, xenograft, and transgenic models of cancer (Table 1). Carriers facilitating delivery have included Superfect (16,51), Fugene6 (32,(35)(36)(37)(38)(39), DOTAP (40), Lipofectamine (33,46), chitosan (54,55), nanoparticles (42), electroporation (41), aptamer targeting (11), transcatheter arterial chemoembolization with Fugene6 and Lipiodol (assists drug retention within the tumor; ref. 56), or simply no carrier (47,49,50,57,58).…”

Section: Preclinical Anticancer Effects Of Dnazymesmentioning

confidence: 99%

Deoxyribozymes as Catalytic Nanotherapeutic Agents

Khachigian

2019

Cancer Research

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RNA-cleaving deoxyribozymes (DNAzymes) are synthetic single-stranded DNA-based catalytic molecules that can be engineered to bind to and cleave target mRNA at predetermined sites. These have been used as therapeutic agents in a range of preclinical cancer models and have entered clinical trials in Europe, China, and Australia. This review surveys regulatory insights into mechanisms of disease brought about by use of catalytic DNA in vitro and in vivo, including recent uses as nanosensors, nanoflowers, and nanosponges, and the emerging role of adaptive immunity underlying DNAzyme inhibition of cancer growth. DNAzymes represent a promising new class of nucleic acid-based therapeutics in cancer. This article discusses mechanistic and therapeutic insights brought about by DNAzyme use as nanotools and reagents in a range of basic science, experimental therapeutic and clinical applications. Current limitations and future perspectives are also discussed.

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“…All animal studies were granted ethical approval by the Institutional Animal Care and Use Committee. Following this, rat carotid artery balloon injury was performed on 10 rats as previously described and the 10 remaining rats were the controls ( 17 ). The left common, external and internal carotid arteries were dissected, and vascular injury was administered to the left common carotid artery using an A Baxter 2-Fr balloon catheter (Baxter International, Deerfield, IL, USA).…”

Section: Methodsmentioning

confidence: 99%

WWC3 inhibits intimal proliferation following vascular injury via the Hippo signaling pathway

Chen

Gui-nan

2018

Mol Med Report

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The Hippo signaling pathway is involved in the formation and development of the cardiovascular system. In the present study, the effects of WWC family member 3 (WWC3) on vascular smooth muscle cells (VSMCs) following injury were investigated, in addition to the associated mechanisms underlying this process. Platelet-derived growth factor BB (PDGF-BB) was used as a cell injury factor, and rats with balloon injuries were used as a model of carotid intimal injury. Furthermore, the expression levels of WWC3 in VSMCs and arteries post-injury were investigated, in addition to the effect of WWC3 on the proliferation and migration of VSMCs. The results demonstrated that following injury, WWC3 expression was suppressed in VSMCs and the rat carotid artery, and the activity of the Hippo signaling pathway was significantly downregulated. In addition, the expression of YY1-associated protein-1 (YAP) and a number of its downstream target genes, including connective tissue growth factor (CTGF), were enhanced, thus enhancing the proliferation and migration of VSMCs. Knockdown of WWC3 suppressed the levels of large tumor suppressor kinase 1 (LATS1) expression and YAP phosphorylation, and the expression of YAP, CTGF and cyclin E was subsequently enhanced, thus promoting cell proliferation and migration. Similar results were obtained following overexpression of WWC3. Treatment with PDGF-BB was revealed to suppress the proliferation and migration of VSMCs transfected with the WWC3 plasmid, compared with VSMCs transfected with an empty vector. The present study demonstrated that WWC3 may interact with LATS1 in order to upregulate the Hippo signaling pathway via co-immunoprecipitation and enhancement of the phosphorylation of LATS1, in addition to the corresponding suppression of the nuclear import of YAP. However, VSMCs transfected with WWC3 plasmid with a deletion of the WW domain fail to exhibit this effect. These results suggested that WWC3 expression is downregulated in VSMCs during neointimal hyperplasia following injury (PDGF-BB stimulation or balloon injury). WWC3 upregulates the activity of the Hippo signaling pathway, and weakens the proliferation and migration of VSMCs. Furthermore, the results of the present study suggested that WWC3 may interact with LATS1 to promote the phosphorylation of YAP and reduce its nuclear translocation, upregulate the activity of the Hippo pathway, and suppress the proliferation and migration of VSMCs following injury.

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DNA Enzyme ED5 Depletes Egr-1 and Inhibits Neointimal Hyperplasia in Rats

Cited by 7 publications

References 77 publications

Src tyrosine kinase mediates endothelin-1-induced early growth response protein-1 expression via MAP kinase-dependent pathways in vascular smooth muscle cells

Src tyrosine kinase mediates endothelin-1-induced early growth response protein-1 expression via MAP kinase-dependent pathways in vascular smooth muscle cells

Deoxyribozymes as Catalytic Nanotherapeutic Agents

WWC3 inhibits intimal proliferation following vascular injury via the Hippo signaling pathway

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