Transfected Early Growth Response Gene-1 DNA Enzyme Prevents Stenosis and Occlusion of Autogenous Vein GraftIn Vivo

Abstract

The aim of this study was to detect the inhibitory action of the early growth response gene-1 DNA enzyme (EDRz) as a carrying agent by liposomes on vascular smooth muscle cell proliferation and intimal hyperplasia. An autogenous vein graft model was established. EDRz was transfected to the graft vein. The vein graft samples were obtained on each time point after surgery. The expression of the EDRz transfected in the vein graft was detected using a fluorescent microscope. Early growth response gene-1 (Egr-1) mRNA was measured using reverse transcription-PCR and in situ hybridization. And the protein expression of Egr-1 was detected by using western blot and immunohistochemistry analyses. EDRz was located at the media of the vein graft from 2 to 24 h, 7 h after grafting. The Egr-1 protein was mainly located in the medial VSMCs, monocytes, and endothelium cells during the early phase of the vein graft. The degree of VSMC proliferation and thickness of intima were obviously relieved compared with the no-gene therapy group. EDRz can reduce Egr-1 expression in autogenous vein grafts, effectively restrain VSMC proliferation and intimal hyperplasia, and prevent vascular stenosis and occlusion after vein graft.

DNA enzymes as potential therapeutics: towards clinical application of 10-23 DNAzymes

“…Moreover, ED5 Dz was able to prevent stenosis and occlusion of autogenous vein graft in rats due to the reduction of Egr-1 expression in autogenous vein grafts, effectively restraining VSMC proliferation and intimal hyperplasia [126].…”

“…A key mediator of oxidative stress by affecting apoptosis signal-regulating kinase 1 and MAPK kinase activities; its expression is stimulated in heart tissue after acute myocardial infarction [120] Early growth response-1 A zinc finger transcription factor upregulated by mechanical injury to vascular SMCs and endothelial cells [121][122][123]125,126] c-jun The protein is involved in regulating proliferation, transformation and apoptosis; it contains 'leucine zipper' domain and forms homo-and heterodimers resulting in AP-1 factor formation [42,121,124,127] c-myc oncogene C-myc, c-fos and c-myb oncogenes provide attractive targets for prevention of restenosis as they are involved in SMC proliferation and migration as well as deposition of extracellular matrix after post-vascular injury [128] Inflammatory diseases c-jun c-jun/AP-1 can be activated by many extracellular stimulators including viral infections and can initiate and enhance the transcription of antiviral agents, which can cause significant inflammation, and appears to have an important role in virus infections and replications. [129] iNOS iNOS is expressed only after induction by inflammatory mediators such as lipopolysaccharides, IL-1 and TNF-a [130,131] TGF-b1 TGF-b regulates cell proliferation, differentiation and immune reaction, one of the most important tasks being regulation of extracellular matrix accumulation; inhibition of mesangial TGF-b expression is one of therapeutic strategies to prevent renal fibrosis [132] GATA-3 Transcription factor GATA-3 plays an important role in Th2 cell activation, but also in the regulation of other cell types involved in bronchial asthma, including mast cells, eosinophils and epithelial cells [33,34,[133][134][135] CNS diseases XT-1 XT-1 is crucial for biosynthesis of glycosylated proteoglycans in the scar after spinal cord injury [136,137] HD gene Selective loss of neurons in HD is caused by abnormal expansion of the CAG triplet (> 36 repeats) of the HD gene techniques and chemotherapy.…”

Deoxyribozymes as Catalytic Nanotherapeutic Agents

“…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). EDRz also reduced formation of abdominal aortic aneurysm in rats, suppressing Egr-1, matrix metalloproteinase (MMP)-2, and MMP-9 levels (34).…”

“…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).…”

Early growth response factor‑1 DNA enzyme 1 inhibits the formation of abdominal aortic aneurysm in rats

“…Early growth response factor 1 (Egr-1) is a zinc finger transcription factor and member of the early gene family. Egr-1 participates in various pathophysiologic processes, such as cell proliferation, differentiation, and apoptosis ( 5 ), inflammatory reaction ( 6 ), thrombosis ( 7 ), and extracellular matrix degradation and synthesis ( 8 ). Egr-1 expression can be rapidly induced by various stimulating factors, such as growth factors, proinflammatory cytokines, lipopolysaccharides, hypoxia, shear stress, and vascular damage.…”