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Decreases in $Casz1$ mRNA by an siRNA Complex Do not Alter Blood Pressure in Mice

  • Ji, Su-Min (Department of Biomedical Engineering, Kyung Hee University School of Medicine) ;
  • Shin, Young-Bin (Department of Biomedical Engineering, Kyung Hee University School of Medicine) ;
  • Park, So-Yon (Department of Biomedical Engineering, Kyung Hee University School of Medicine) ;
  • Lee, Hyeon-Ju (Department of Biomedical Engineering, Kyung Hee University School of Medicine) ;
  • Oh, Berm-Seok (Department of Biomedical Engineering, Kyung Hee University School of Medicine)
  • 투고 : 2011.12.21
  • 심사 : 2012.02.08
  • 발행 : 2012.03.31

초록

Recent genomewide association studies of large samples have identified genes that are associated with blood pressure. The Global Blood Pressure Genetics (Global BPgen) and Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) consortiums identified 14 loci that govern blood pressure on a genomewide significance level, one of which is $CASZ1$ confirmed in both Europeans and Asians. $CASZ1$ is a zinc finger transcription factor that controls apoptosis and cell fate and suppresses neuroblastoma tumor growth by reprogramming gene expression, like a tumor suppressor. To validate the function of $CASZ1$ in blood pressure, we decreased $Casz1$ mRNA levels in mice by siRNA. $Casz1$ siRNA reduced mRNA levels by 59% in a mouse cell line. A polyethylenimine-mixed siRNA complex was injected into mouse tail veins, reducing $Casz1$ mRNA expression to 45% in the kidney. However, blood pressure in the treated mice was unaffected, despite a 55% reduction in $Casz1$ mRNA levels in the kidney on multiple siRNA injections daily. Even though $Casz1$ siRNA-treated mice did not experience any significant change in blood pressure, our study demonstrates the value of $in$ $vivo$ siRNA injection in analyzing the function of candidate genes identified by genomewide association studies.

키워드

참고문헌

  1. Liu Z, Yang X, Tan F, Cullion K, Thiele CJ. Molecular cloning and characterization of human Castor, a novel human gene upregulated during cell differentiation. Biochem Biophys Res Commun 2006;344:834-844. https://doi.org/10.1016/j.bbrc.2006.03.207
  2. Yuan ZR, Wang R, Solomon J, Luo X, Sun H, Zhang L, et al. Identification and characterization of survival-related gene, a novel cell survival gene controlling apoptosis and tumorigenesis. Cancer Res 2005;65:10716-10724. https://doi.org/10.1158/0008-5472.CAN-05-2176
  3. Levy D, Ehret GB, Rice K, Verwoert GC, Launer LJ, Dehghan A, et al. Genome-wide association study of blood pressure and hypertension. Nat Genet 2009;41:677-687. https://doi.org/10.1038/ng.384
  4. Newton-Cheh C, Johnson T, Gateva V, Tobin MD, Bochud M, Coin L, et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet 2009;41:666-676. https://doi.org/10.1038/ng.361
  5. Psaty BM, O'Donnell CJ, Gudnason V, Lunetta KL, Folsom AR, Rotter JI, et al. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium: design of prospective meta-analyses of genome- wide association studies from 5 cohorts. Circ Cardiovasc Genet 2009;2:73-80. https://doi.org/10.1161/CIRCGENETICS.108.829747
  6. Takeuchi F, Isono M, Katsuya T, Yamamoto K, Yokota M, Sugiyama T, et al. Blood pressure and hypertension are associated with 7 loci in the Japanese population. Circulation 2010;121:2302-2309. https://doi.org/10.1161/CIRCULATIONAHA.109.904664
  7. Ho JE, Levy D, Rose L, Johnson AD, Ridker PM, Chasman DI. Discovery and replication of novel blood pressure genetic loci in the Women's Genome Health Study. J Hypertens 2011;29:62-69. https://doi.org/10.1097/HJH.0b013e3283406927
  8. Kato N, Takeuchi F, Tabara Y, Kelly TN, Go MJ, Sim X, et al. Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in east Asians. Nat Genet 2011;43: 531-538. https://doi.org/10.1038/ng.834
  9. Davey RA, MacLean HE. Current and future approaches using genetically modified mice in endocrine research. Am J Physiol Endocrinol Metab 2006;291: E429-E438. https://doi.org/10.1152/ajpendo.00124.2006
  10. Rubinson DA, Dillon CP, Kwiatkowski AV, Sievers C, Yang L, Kopinja J, et al. A lentivirus-based system to functionally silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference. Nat Genet 2003;33:401-406. https://doi.org/10.1038/ng1117
  11. Xie FY, Woodle MC, Lu PY. Harnessing in vivo siRNA delivery for drug discovery and therapeutic development. Drug Discov Today 2006;11:67-73. https://doi.org/10.1016/S1359-6446(05)03668-8
  12. Musunuru K, Strong A, Frank-Kamenetsky M, Lee NE, Ahfeldt T, Sachs KV, et al. From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature 2010;466:714-719. https://doi.org/10.1038/nature09266
  13. Shim MS, Kwon YJ. Efficient and targeted delivery of siRNA in vivo . FEBS J 2010;277:4814-4827. https://doi.org/10.1111/j.1742-4658.2010.07904.x
  14. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001;25:402-408. https://doi.org/10.1006/meth.2001.1262
  15. Alyaudtin RN, Reichel A, Lobenberg R, Ramge P, Kreuter J, Begley DJ. Interaction of poly(butylcyanoacrylate) nanoparticles with the blood-brain barrier in vivo and in vitro . J Drug Target 2001;9:209-221. https://doi.org/10.3109/10611860108997929

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