Abstract
RNA interference (RNAi) is an adaptive defense mechanism through which double-stranded RNAs silence cognate genes in a sequence-specific manner. It has been employed widely as a powerful tool in functional genomics studies, target validation and therapeutic product development. Similarly, the application of small-interfering RNA (siRNA) to the silencing of the disease-causing genes involved in cardiovascular diseases has made great progress. In this overview, we attempt to provide a brief outline of the current understanding of the mechanism of RNAi and its potential application to the cardiovascular system, with particular emphasis on its ability to identify the pathophysiological function of genes related to several important cardiovascular disorders. The prospects of RNAi-based therapeutics, as well as the advantages and potential problems, are also discussed.
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Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC . Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 1998; 391: 806–11.
de Francesco R, Migliaccio G . Challenges and successes in developing new therapies for hepatitis C. Nature 2005; 436: 953–60.
Yin JQ, Gao J, Shao R, Tian WN, Wang J, Wan Y . siRNA agents inhibit oncogene expression and attenuate human tumor cell growth. J Exp Ther Oncol 2003; 3: 1–11.
Drosett Y, Tuschl T . siRNAs: applications in functional genomics and potential as therapeutics. Nat Rev Drug Discov 2004; 3: 319–29.
Zimmermann TS, Lee AC, Akinc A, Bramlage B, Bumcrot D, Fedoruk MN, et al. RNAi-mediated gene silencing in non-human primates. Nature 2006; 441: 111–4.
Soutschek J, Akinc A, Bramlage B, Charisse K, Constien R, Donoghue M, et al. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 2004; 432: 173–8.
Hannon GJ . RNA interference. Nature 2002; 418: 244–51.
Hammond SM, Bernstein E, Beach D, Hannon GJ . An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells. Nature 2000; 404: 293–6.
Carmell MA, Hannon GJ . RNase III enzymes and the initiation of gene silencing. Nat Struct Mol Biol 2004; 11: 214–8.
Matranga C, Tomari Y, Shin C, Bartel DP, Zamore PD . Passenger-strand cleavage facilitates assembly of siRNA into Ago2-containing RNAi enzyme complexes. Cell 2005; 123: 607–20.
Liu J, Carmell MA, Rivas FV, Marsden CG, Thomson JM, Song JJ, et al. Argonaute2 is the catalytic engine of mammalian RNAi. Science 2004; 305: 1437–41.
Ma JB, Yuan YR, Meister G, Pei Y, Tuschl T, Patel DJ . Structural basis for 5′-end-specific recognition of guide RNAby the A. fulgidus Piwi protein. Nature 2005; 434: 666–70.
Zamore PD, Haley B . Ribo-gnome: the big world of small RNAs. Science 2005; 309: 1519–24.
Paddison PJ, Hannon GJ . siRNAs and shRNAs: skeleton keys to the human genome. Curr Opin Mol Ther 2003; 5: 217–24.
Scacheri PC, Rozenblatt-Rosen O, Caplen NJ, Wolfsberg TG, Umayam L, Lee JC, et al. Short interfering RNAs can induce unexpected and divergent changes in the levels of untargeted proteins in mammalian cells. Proc Natl Acad Sci USA 2004; 101: 1892–7.
Santoyo J, Vaquerizas JM, Dopazo J . Highly specific and accurate selection of siRNAs for high-throughout functional assays. Bioinformatics 2005; 21: 1376–82.
Heale BS, Soifer HS, Bowers C, Rossi JJ . siRNA target site secondary structure predictions using local stable substructures. Nucleic Acids Res 2005; 33: e30.
lmen J, Thonberg H, Ljungberg K, Frieden M, Westergaard M, Xu Y, et al. Locked nucleic acid (LNA) mediated improvements in siRNA stability and functionality. Nucleic Acids Res 2005; 33: 439–47.
Amarzguioui M, Rossi JJ, Kim D . Approaches for chemically synthesized siRNA and vector-mediated RNAi. FEBS Lett 2005; 579: 5974–81.
Manoharan M . RNA interference and chemically modified small interfering RNAs. Curr Opin Chem Biol 2004; 8: 570–9.
Kasahara H, Aoki H . Gene silencing using adenoviral RNAi vector in vascular smooth muscle cells and cardiomyocytes. Methods Mol Med 2005; 112: 155–72.
Hashiya N, Aoki M, Tachibana K, Taniyama Y, Yamasaki K, Hiraoka K, et al. Local delivery of E2F decoy oligodeoxynucleotides using ultrasound with microbubble agent (Optison) inhibits intimal hyperplasia after balloon injury in rat carotid artery model. Biochem Biophys Res Commun 2004; 317: 508–14.
Erikson JM, Freeman GL, Chandrasekar B . Ultrasound-targeted antisense oligonucleotide attenuates ischemia/reperfusion-induced myocardial tumor necrosis factor-alpha. J Mol Cell Cardiol 2003; 35: 119–30.
Shohet RV, Chen S, Zhou YT, Wang Z, Meidell RS, Unger RH, et al. Echocardiographic destruction of albumin microbubbles directs gene delivery to the myocardium. Circulation 2000; 101: 2554–6.
Wang ZG, Liang ZY, Ran HT, Ren H, Zhang QX, Huang AL, et al. Ultrasound-mediated microbubble destruction enhances VEGF gene delivery to the infarcted myocardium in rats. Clin Imaging 2004; 28: 395–8.
Kondo I, Ohmori K, Oshita A, Takeuchi H, Fuke S, Shinomiya K, et al. Treatment of acute myocardial infarction by hepatocyte growth factor gene transfer: the first demonstration of myocardial transfer of a “functional” gene using ultrasonic microbubble destruction. J Am Coll Cardiol 2004; 44: 644–53.
Chae SS, Paik JH, Furneaux H, Hla T . Requirement for sphingosine 1--phosphate receptor-1 in tumor angiogenesis demonstrated by in vivo RNA interference. J Clin Invest 2004; 114: 1082–9.
Hamar P, Song E, Kokeny G, Chen A, Ouyang N, Lieberman J . Small interfering RNA targeting Fas protects mice against renal ischemia-reperfusion injury. Proc Natl Acad Sci USA 2004; 101: 14883–8.
Yin JQ, Wan Y . siRNA-mediated gene regulation system. Int J Mol Med 2002; 10: 355–65.
Li Y, Takemura G, Kosai K, Takahashi T, Okada H, Miyata S, et al. Critical roles for the Fas/Fas ligand system in postinfarction ventricular remodeling and heart failure. Circ Res 2004; 17: 627–36.
Song E, Lee SK, Wang J, Ince N, Ouyang N, Min J, et al. RNA interference targeting Fas protects mice from fulminant hepatitis. Nat Med 2003; 9: 347–51.
Bennett MR . Apoptosis of vascular smooth muscle cells in vascular remodelling and atherosclerotic plaque rupture. Cardiovasc Res 1999; 41: 361–8.
Liu HR, Gao E, Hu A, Tao L, Qu Y, Most P, et al. Role of Omi/HtrA2 in apoptotic cell death after myocardial ischemia and reperfusion. Circulation 2005; 111: 90–6.
Blaschke F, Bruemmer D, Yin F, Takata Y, Wang W, Fishbein MC, et al. C-reactive protein induces apoptosis in human coronary vascular smooth muscle cells. Circulation 2004; 110: 579–87.
Kim YO, Park SJ, Balaban RS, Nirenberg M, Kim Y . A functional genomic screen for cardiogenic genes using RNA interference in developing Drosophila embryos. Proc Natl Acad Sci USA 2004; 101: 159–64.
Qian L, Liu J, Bodmer R . Neuromancer Tbx20-related genes (H15/midline) promote cell fate specification and morphogenesis of the Drosophila heart. Dev Biol 2005; 279: 509–24.
Lickert, H, Takeuchi JK, Von BI, Walls JR, McAuliffe F, Adamson SL, et al. Baf60c is essential for function of BAF chromatin remodelling complexes in heart development. Nature 2004; 432: 107–12.
Chartier A, Zaffran S, Astier M, Semeriva M, Gratecos D . Pericardin, a Drosophila type IV collagen-like protein is involved in the morphogenesis and maintenance of the heart epithelium during dorsal ectoderm closure. Development 2002; 129: 3241–53.
Kizer JR, Wachtell K, Lehto M, Julius S, Beevers G, de Faire U, et al. Stroke reduction in hypertensive adults with cardiac hypertrophy randomized to losartan versus atenolol: the losartan intervention for endpoint reduction in hypertension study. Hypertension 2005; 45: 46–52.
Watanable T, Barker TA, Berk BC . Angiotensin II and the endothelium: diverse signals and effects. Hypertension 2005; 45: 163–9.
Gurley SB, Le TH, Coffman TM . Gene-targeting studies of the renin-angiotensin system: mechanisms of hypertension and cardiovascular disease. Cold Spring Harb Symp Quant Biol 2002; 67: 451–7.
Vazquez J, Correa de Adjounian MF, Sumners C, Sumners C, Gonzalez A, Diez-Freire C, et al. Selective silencing of angiotensin receptor subtype 1a (AT1aR) by RNA interference. Hypertension 2005; 45: 115–9.
Chen Y, Currie RW . Small interfering RNA knocks down heat shock factor-1 (HSF-1) and exacerbates pro-inflammatory activation of NF-kappaB and AP-1 in vascular smooth muscle cells. Cardiovasc Res 2006; 69: 66–75.
Sward K, Mita M, Wilson DP, Deng JT, Susnjar M, Walsh MP . The role of RhoA and Rho-associated kinase in vascular smooth muscle contraction. Curr Hypertens Rep 2003; 5: 66–72.
Bi D, Nishimura J, Niiro N, Hirano K, Kanaide H . Contractile properties of the cultured vascular smooth muscle cells. The crucial role played by RhoA in the regulation of contractility. Circ Res 2005; 96: 890–7.
Hansson, SM, Bernstein E, Beach D, Hannon GJ . An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells. Nature 2002; 404: 293–6.
Collins T, Cybulsky MI . NF-kappaB: pivotal mediator or innocent bystander in atherogenesis?. J Clin Invest 2001; 101: 255–64.
Dwarakanath RS, Sahar S, Reddy MA, Castanotto D, Rossi JJ, Natarajan R . Regulation of monocyte chemoattractant protein-1 by the oxidized lipid, 13-hydroperoxyoctadecadienoic acid, in vascular smooth muscle cells via nuclear factor-kappa B (NF-kappaB). J Mol Cell Cardiol 2004; 36: 585–95.
Kobashi C, Urakaze M, Kishida M, Kibayashi E, Kobayashi H, Kihara S, et al. Adiponectin inhibits endothelial synthesis of interleukin-8. Circ Res 2005; 97: 1216–9.
Liu X, Li T, Sun S, Yang Y . Role of myofibrillogenesis regulator-1 in myocardial hypertrophy. Am J Physiol Heart Circ Physiol 2005; 290: H279–85.
Si X, Rahmarni M, Yuan J, Lou H . Detection of cardiac signaling in the injured and hypertrophied heart. Methods Mol Med 2005; 112: 291–303.
Pedram A, Razandi M, Aitkenhead M, Levin ER . Estrogen inhibits cardiomyocyte hypertrophy in vitro: Antagonism of calcineurin-related hypertrophy through induction of MCIP1. J Biol Chem 2005; 280: 26339–48.
Liu P, Martino T, Opavsky MA, Penninger J . Viral myocarditis: balance between viral infection and immune response. Can J Cardiol 1996; 12: 935–43.
Yang D, Yu J, Luo Z, Carthy CM, Wilson JE, Liu Z, et al. Viral myocarditis identification of five differentially expressed genes in coxsackievirus B3-infected mouse heart. Circ Res 1999; 84: 704–12.
Schubert S, Grunert HP, Zeichhardt H, Werk D, Erdmann VA, Kurreck J . Maintaining inhibition: siRNA double expression vectors against coxsackieviral RNAs. J Mol Biol 2005; 346: 457–65.
Yuan J, Cheung PK, Zhang HM, Chau D, Yang D . Inhibition of coxsackievirus B3 replication by small interfering RNAs requires perfect sequence match in the central region of the viral positive strand. J Virol 2005; 79: 2151–9.
Hobai IA, O'Rourke B . Decreased sarcoplasmic reticulum calcium content is responsible for defective excitation-contraction coupling in canine heart failure. Circulation 2003; 103: 1577–84.
Watanabe A, Arai M, Yamazaki M, Koitabashi N, Wuytack F, Kurabayashi M . Phospholamban ablation by RNA interference increase Ca2+ uptake into rat cardiac myocyte sarcoplasmic reticulum. J Mol Cell Cardiol 2004; 37: 691–8.
Liu TG, Yin Q, Shang BY, Min Z, He HW, Jiang JM, et al. Silencing of hdm2 oncogene by siRNA inhibits p53-dependent human breast cancer. Cancer Gene Ther 2004; 11: 748–56.
Aigner A . Gene silencing through RNA interference (RNAi) in vivo: strategies based on the direct application of siRNAs. J Biotechnol 2006; 124: 12–5.
Lu PY, Xie F, Woodle MC . In vivo application of RNA interference: from functional genomics to therapeutics. Adv Genet 2005; 54: 117–42.
Barik S . Development of gene-specific double-stranded RNA drugs. Ann Med 2004; 36: 540–51.
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Project partly supported by the Hundred Talents Program of the Chinese Academy of Sciences, and the High-Tech Project Foundation (863 project) (No 2002BA711A01-22).
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Tang, Y., Ge, Yz. & Yin, J. Exploring in vitro roles of siRNA in cardiovascular disease. Acta Pharmacol Sin 28, 1–9 (2007). https://doi.org/10.1111/j.1745-7254.2007.00491.x
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DOI: https://doi.org/10.1111/j.1745-7254.2007.00491.x
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