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

Wang,Shi; Dong,Haipeng; Liu,Chengwei; Xu,Guichao; Hu,Xinhua; Fan,Yichuan; Chen,Liting

doi:10.3892/etm.2018.6139

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

Authors:
- Shi Wang
- Haipeng Dong
- Chengwei Liu
- Guichao Xu
- Xinhua Hu
- Yichuan Fan
- Liting Chen
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Affiliations: Department of Stomatology, The First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang 154002, P.R. China, Department of Cardiothoracic Vascular Surgery, Affiliated Hospital of Beihua University, Jilin City, Jilin 132000, P.R. China, Division of Vascular Surgery, The First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang 154002, P.R. China, Department of Surgery, First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110000, P.R. China, Department of Emergency, Affiliated Hospital of Beihua University, Jilin City, Jilin 132000, P.R. China
Published online on: May 8, 2018 https://doi.org/10.3892/etm.2018.6139
Pages: 141-148
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The aim of the present study was to characterize the effects of early growth response factor‑1 DNA enzyme (EDRz) in a rat abdominal aortic aneurysm (AAA) model to determine the mechanism by which EDRz inhibits AAA and affects the formation of AAA by regulating the activity of matrix metalloproteinase (MMP)‑2 and MMP‑9. EDRz was transfected into the abdominal aorta of rats using the jetPRIME transfection reagent following infusion with elastase. Fluorescent microscopy, hematoxylin and eosin staining, ultrastructural analysis, reverse transcription‑quantitative polymerase chain reaction, western blotting and immunohistochemical analysis were performed to characterize the response to EDRz. The EDRz group showed minimal aneurysm formation when compared with the control group, with significantly lower aortic diameter expansion (2.5±0.1 vs. 3.5±0.1 mm; P<0.05). Early growth response factor 1 (Egr‑1) mRNA and protein levels were significantly decreased in the EDRz group, as expected. The decrease in Egr‑1 was accompanied by decreases in the mRNA and protein levels of MMP‑2 and MMP‑9 (P<0.05). Transfection of the Egr‑1 specific synthetic DNA enzyme EDRz significantly reduced AAA following elastase infusion in rats, at least in part due to the decreased expression of downstream MMP‑2 and MMP‑9.

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1	Grøndal N, Søgaard R and Lindholt JS: Baseline prevalence of abdominal aortic aneurysm, peripheral arterial disease and hypertension in men aged 65–74 years from a population screening study (VIVA trial). Br J Surg. 102:902–906. 2015. View Article : Google Scholar : PubMed/NCBI
2	Benson RA, Poole R, Murray S, Moxey P and Loftus IM: Screening results from a large United Kingdom abdominal aortic aneurysm screening center in the context of optimizing United Kingdom national abdominal aortic aneurysm screening programme protocols. J Vasc Surg. 63:301–304. 2016. View Article : Google Scholar : PubMed/NCBI
3	Shin S, Cho YP, Jun H, Park H, Hong HN and Kwon TW: Transglutaminase type 2 in human abdominal aortic aneurysm is a potential factor in the stabilization of extracellular matrix. J Vasc Surg. 57:1362–1370. 2013. View Article : Google Scholar : PubMed/NCBI
4	Tang L, Cong Z, Hao S, Li P, Huang H, Shen Y, Li K and Jing H: Protective effect of melatonin on the development of abdominal aortic aneurysm in a rat model. J Surg Res. 209:266–278.e1. 2017. View Article : Google Scholar : PubMed/NCBI
5	Pagel JI and Deindl E: Early growth response 1-a transcription factor in the crossfire of signal transduction cascades. Indian J Biochem Biophys. 48:226–235. 2011.PubMed/NCBI
6	Wang NP, Pang XF, Zhang LH, Tootle S, Harmouche S and Zhao ZQ: Attenuation of inflammatory response and reduction in infarct size by postconditioning are associated with downregulation of early growth response 1 during reperfusion in rat heart. Shock. 41:346–354. 2014. View Article : Google Scholar : PubMed/NCBI
7	Liu C, Zhang X, Wang S, Cheng M, Liu C, Wang S, Hu X and Zhang Q: Transfected early growth response gene-1 DNA enzyme prevents stenosis and occlusion of autogenous vein graft in vivo. Biomed Res Int. 2013:3104062013.PubMed/NCBI
8	Ha YM, Lee DH, Kim M and Kang YJ: High glucose induces connective tissue growth factor expression and extracellular matrix accumulation in rat aorta vascular smooth muscle cells via extracellular signal-regulated kinase 1/2. Korean J Physiol Pharmacol. 17:307–314. 2013. View Article : Google Scholar : PubMed/NCBI
9	Charolidi N, Pirianov G, Torsney E, Pearce S, Laing K, Nohturfft A and Cockerill GW: Pioglitazone identifies a new target for aneurysm treatment: Role of Egr1 in an experimental murine model of aortic aneurysm. J Vasc Res. 52:81–93. 2015. View Article : Google Scholar : PubMed/NCBI
10	Shin IS, Kim JM, Kim KL, Jang SY, Jeon ES, Choi SH, Kim DK, Suh W and Kim YW: Early growth response factor-1 is associated with intraluminal thrombus formation in human abdominal aortic aneurysm. J Am Coll Cardiol. 53:792–799. 2009. View Article : Google Scholar : PubMed/NCBI
11	Yamashiro Y, Papke CL, Kim J, Ringuette LJ, Zhang QJ, Liu ZP, Mirzaei H, Wagenseil JE, Davis EC and Yanagisawa H: Abnormal mechanosensing and cofilin activation promote the progression of ascending aortic aneurysms in mice. Sci Signal. 8:ra1052015. View Article : Google Scholar : PubMed/NCBI
12	Kong L, Shen X, Lin L, Leitges M, Rosario R, Zou YS and Yan SF: PKCβ promotes vascular inflammation and acceleration of atherosclerosis in diabetic ApoE null mice. Arterioscler Thromb Vasc Biol. 33:1779–1787. 2013. View Article : Google Scholar : PubMed/NCBI
13	Morawietz H, Ma YH, Vives F, Wilson E, Sukhatme VP, Holtz J and Ives HE: Rapid induction and translocation of Egr-1 in response to mechanical strain in vascular smooth muscle cells. Circ Res. 84:678–687. 1999. View Article : Google Scholar : PubMed/NCBI
14	Fu M, Zhu X, Zhang J, Liang J, Lin Y, Zhao L, Ehrengruber MU and Chen YE: Egr-1 target genes in human endothelial cells identified by microarray analysis. Gene. 315:33–41. 2003. View Article : Google Scholar : PubMed/NCBI
15	Yuan K, Liang W and Zhang J: A comprehensive analysis of differentially expressed genes and pathways in abdominal aortic aneurysm. Mol Med Rep. 12:2707–2714. 2015. View Article : Google Scholar : PubMed/NCBI
16	Li J, Wang N, Luo Q and Wan L: The 10–23 DNA enzyme generated by a novel expression vector mediate inhibition of taco expression in macrophage. Oligonucleotides. 20:61–68. 2010. View Article : Google Scholar : PubMed/NCBI
17	Lam CH and Perrin DM: Introduction of guanidinium-modified deoxyuridine into the substrate binding regions of DNAzyme 10–23 to enhance target affinity: Implications for DNAzyme design. Bioorg Med Chem Lett. 20:5119–5122. 2010. View Article : Google Scholar : PubMed/NCBI
18	Pagel JI, Ziegelhoeffer T, Heil M, Fischer S, Fernández B, Schaper W, Preissner KT and Deindl E: Role of early growth response 1 in arteriogenesis: impact on vascular cell proliferation and leukocyte recruitment in vivo. Thromb Haemost. 107:562–574. 2012. View Article : Google Scholar : PubMed/NCBI
19	Dickinson MG, Kowalski PS, Bartelds B, Borgdorff MA, van der Feen D, Sietsma H, Molema G, Kamps JA and Berger RM: A critical role for Egr-1 during vascular remodelling in pulmonary arterial hypertension. Cardiovasc Res. 103:573–584. 2014. View Article : Google Scholar : PubMed/NCBI
20	Huang M, Satchell L, Duhadaway JB, Prendergast GC and Laury-Kleintop LD: RhoB links PDGF signaling to cell migration by coordinating activation and localization of Cdc42 and Rac. J Cell Biochem. 112:1572–1584. 2011. View Article : Google Scholar : PubMed/NCBI
21	Uchida K, Sasahara M, Morigami N, Hazama F and Kinoshita M: Expression of platelet-derived growth factor B-chain in neointimal smooth muscle cells of balloon injured rabbit femoral arteries. Atherosclerosis. 124:9–23. 1996. View Article : Google Scholar : PubMed/NCBI
22	Iyoda T, Zhang F, Sun L, Hao F, Schmitz-Peiffer C, Xu X and Cui MZ: Lysophosphatidic acid induces early growth response-1 (Egr-1) protein expression via protein kinase Cδ-regulated extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) activation in vascular smooth muscle cells. J Biol Chem. 287:22635–22642. 2012. View Article : Google Scholar : PubMed/NCBI
23	Wu Y, Han W and Liu GN: A DNA enzyme targeting Egr-1 inhibits rat vascular smooth muscle cell proliferation by down-regulation of cyclin D1 and TGF-beta1. Braz J Med Biol Res. 43:17–24. 2010. View Article : Google Scholar : PubMed/NCBI
24	Longo GM, Xiong W, Greiner TC, Zhao Y, Fiotti N and Baxter BT: Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. J Clin Invest. 110:625–632. 2002. View Article : Google Scholar : PubMed/NCBI
25	Yan YF, Pei JF, Zhang Y, Zhang R, Wang F, Gao P, Zhang ZQ, Wang TT, She ZG, Chen HZ and Liu DP: The paraoxonase gene cluster protects against abdominal aortic aneurysm formation. Arterioscler Thromb Vasc Biol. 37:291–300. 2017. View Article : Google Scholar : PubMed/NCBI
26	Chabasse C, Siefert SA, Chaudry M, Hoofnagle MH, Lal BK and Sarkar R: Recanalization and flow regulate venous thrombus resolution and matrix metalloproteinase expression in vivo. J Vasc Surg Venous Lymphat Disord. 3:64–74. 2015. View Article : Google Scholar : PubMed/NCBI
27	Tanaka A, Hasegawa T, Chen Z, Okita Y and Okada K: A novel rat model of abdominal aortic aneurysm using a combination of intraluminal elastase infusion and extraluminal calcium chloride exposure. J Vasc Surg. 50:1423–1432. 2009. View Article : Google Scholar : PubMed/NCBI
28	Pezet M, Jacob MP, Escoubet B, Gheduzzi D, Tillet E, Perret P, Huber P, Quaglino D, Vranckx R, Li DY, et al: Elastin haploinsufficiency induces alternative aging processes in the aorta. Rejuvenation Res. 11:97–112. 2008. View Article : Google Scholar : PubMed/NCBI
29	Shin SY, Kim JH, Baker A, Lim Y and Lee YH: Transcription factor Egr-1 is essential for maximal matrix metalloproteinase-9 transcription by tumor necrosis factor alpha. Mol Cancer Res. 8:507–519. 2010. View Article : Google Scholar : PubMed/NCBI
30	Harja E, Chang JS, Lu Y, Leitges M, Zou YS, Schmidt AM and Yan SF: Mice deficient in PKCbeta and apolipoprotein E display decreased atherosclerosis. FASEB J. 23:1081–1091. 2009. View Article : Google Scholar : PubMed/NCBI
31	Haas TL, Stitelman D, Davis SJ, Apte SS and Madri JA: Egr-1 mediates extracellular matrix-driven transcription of membrane type 1 matrix metalloproteinase in endothelium. J Biol Chem. 274:22679–22685. 1999. View Article : Google Scholar : PubMed/NCBI
32	Sho E, Sho M, Singh TM, Nanjo H, Komatsu M, Xu C, Masuda H and Zarins CK: Arterial enlargement in response to high flow requires early expression of matrix metalloproteinases to degrade extracellular matrix. Exp Mol Pathol. 73:142–153. 2002. View Article : Google Scholar : PubMed/NCBI