Targeting of hepatic angiotensinogen using chemically modified siRNAs results in significant and sustained blood pressure lowering in a rat model of hypertension

Hypertension Research

Volumn 37, Issue 5, 2014, Pages 405-412

  Olearczyk, Jeffrey ^a   Gao, Sheng ^a   Eybye, Marianne ^a   Yendluri, Satyasri ^b   Andrews, Lori ^b   Bartz, Steven ^a   Cully, Doris ^a   Tadin Strapps, Marija ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

^b Sirna Therapeutics Inc   (United States)

Author keywords

angiotensinogen; blood pressure lowering; lipid nanoparticles; siRNA targeting

Indexed keywords

ANGIOTENSINOGEN; LIPID NANOPARTICLE; MESSENGER RNA; NANOPARTICLE; SMALL INTERFERING RNA; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; BLOOD PRESSURE; CHEMICAL MODIFICATION; CONTROLLED STUDY; ENZYME INHIBITION; GENE DELIVERY SYSTEM; GENE SILENCING; GENE TARGETING; HYPERTENSION; IN VIVO STUDY; LIVER; LIVER CELL; LIVER FUNCTION; MALE; NANOENCAPSULATION; NONHUMAN; PLASMA; PROTEIN BLOOD LEVEL; RAT; REDUCTION; SPONTANEOUSLY HYPERTENSIVE RAT; SPRAGUE DAWLEY RAT; ANIMAL; DISEASE MODEL; GENETICS; METABOLISM; PATHOPHYSIOLOGY; PHYSIOLOGY; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM;

ANGIOTENSINOGEN; ANIMALS; BLOOD PRESSURE; DISEASE MODELS, ANIMAL; HEPATOCYTES; HYPERTENSION; LIVER; MALE; NANOPARTICLES; RATS; RATS, INBRED SHR; RATS, SPRAGUE-DAWLEY; RENIN-ANGIOTENSIN SYSTEM; RNA, SMALL INTERFERING;

EID: 84899857070     PISSN: 09169636     EISSN: 13484214     Source Type: Journal    
DOI: 10.1038/hr.2013.155     Document Type: Article

References (55)

1. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: Analysis of worldwide data. Lancet 2005; 365: 217-223
2. Atlas SA. The renin-Angiotensin aldosterone system: Pathophysiological role and pharmacologic inhibition. J Manag Care Pharm 2007; 13(Suppl B), 9-20
3. Corvol P, Soubrier F, Jeunemaitre X. Molecular genetics of the renin-Angiotensinaldosterone system in human hypertension. Pathol Biol (Paris) 1997; 45: 229-239
4. Brasier AR, Li J. Mechanisms for inducible control of angiotensinogen gene transcription. Hypertension 1996; 27(Pt 2), 465-475
5. Morgan L, Broughton Pipkin F, Kalsheker N. Angiotensinogen: Molecular biology, biochemistry and physiology. Int J Biochem Cell Biol 1996; 28: 1211-1222
6. Gould AB, Green D. Kinetics of the human renin and human substrate reaction. Cardiovasc Res 1971; 5: 86-89
7. Fasola AF, Martz BL, Helmer OM. Renin activity during supine exercise in normotensives and hypertensives. J Appl Physiol 1966; 21: 1709-1712
8. Walker WG, Whelton PK, Saito H, Russell RP, Hermann J. Relation between blood pressure and renin, renin substrate, angiotensin II, aldosterone and urinary sodium and potassium in 574 ambulatory subjects. Hypertension 1979; 1: 287-291
9. Watt GC, Harrap SB, Foy CJ, Holton DW, Edwards HV, Davidson HR, Connor JM, Lever AF, Fraser R. Abnormalities of glucocorticoid metabolism and the renin-Angiotensin system: A four-corners approach to the identification of genetic determinants of blood pressure. J Hypertens 1992; 10: 473-482
10. Gardes J, Bouhnik J, Clauser E, Corvol P, Menard J. Role of angiotensinogen in blood pressure homeostasis. Hypertension 1982; 4: 185-189
11. Menard J, el Amrani AI, Savoie F, Bouhnik J. Angiotensinogen: An attractive and underrated participant in hypertension and inflammation. Hypertension 1991; 18: 705-707
12. Kim HS, Krege JH, Kluckman KD, Hagaman JR, Hodgin JB, Best CF, Jennette JC, Coffman TM, Maeda N, Smithies O. Genetic control of blood pressure and the angiotensinogen locus. Proc Natl Acad Sci USA 1995; 92: 2735-2739
13. Kimura S, Mullins JJ, Bunnemann B, Metzger R, Hilgenfeldt U, Zimmermann F, Jacob H, Fuxe K, Ganten D, Kaling M. High blood pressure in transgenic mice carrying the rat angiotensinogen gene. Embo J 1992; 11: 821-827
14. Tanimoto K, Sugiyama F, Goto Y, Ishida J, Takimoto E, Yagami K, Fukamizu A, Murakami K. Angiotensinogen-deficient mice with hypotension. J Biol Chem 1994; 269: 31334-31337
15. Makino N, Sugano M, Ohtsuka S, Sawada S. Intravenous injection with antisense oligodeoxynucleotides against angiotensinogen decreases blood pressure in spontaneously hypertensive rats. Hypertension 1998; 31: 1166-1170
16. Phillips MI. Gene therapy for hypertension: Sense and antisense strategies. Expert Opin Biol Ther 2001; 1: 655-662
17. Aagaard L, Rossi JJ. RNAi therapeutics: Principles, prospects and challenges. Adv Drug Deliv Rev 2007; 59: 75-86
18. Tomari Y, Zamore PD. Perspective: Machines for RNAi. Genes Dev. 2005; 19: 517-529
19. Frank-Kamenetsky M, Grefhorst A, Anderson NN, Racie TS, Bramlage B, Akinc A, Butler D, Charisse K, Dorkin R, Fan Y, Gamba-Vitalo C, Hadwiger P, Jayaraman M, John M, Jayaprakash KN, Maier M, Nechev L, Rajeev KG, Read T, Rohl I, Soutschek J, Tan P, Wong J, Wang G, Zimmermann T, de Fougerolles A, Vornlocher HP, Langer R, Anderson DG, Manoharan M, Koteliansky V, Horton JD, Fitzgerald K. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc Natl Acad Sci USA 2008; 105: 11915-11920
20. Khoury M, Louis-Plence P, Escriou V, Noel D, Largeau C, Cantos C, Scherman D, Jorgensen C, Apparailly F. Efficient new cationic liposome formulation for systemic delivery of small interfering RNA silencing tumor necrosis factor alpha in experimental arthritis. Arthritis Rheum 2006; 54: 1867-1877
21. Morrissey DV, Blanchard K, Shaw L, Jensen K, Lockridge JA, Dickinson B, McSwiggen JA, Vargeese C, Bowman K, Shaffer CS, Polisky BA, Zinnen S. Activity of stabilized short interfering RNA in a mouse model of hepatitis B virus replication. Hepatology 2005; 41: 1349-1356
22. Sonoke S, Ueda T, Fujiwara K, Sato Y, Takagaki K, Hirabayashi K, Ohgi T, Yano J. Tumor regression in mice by delivery of Bcl-2 small interfering RNA with pegylated cationic liposomes. Cancer Res 2008; 68: 8843-8851
23. Zimmermann TS, Lee AC, Akinc A, Bramlage B, Bumcrot D, Fedoruk MN, Harborth J, Heyes JA, Jeffs LB, John M, Judge AD, Lam K, McClintock K, Nechev LV, Palmer LR, Racie T, Rohl I, Seiffert S, Shanmugam S, Sood V, Soutschek J, Toudjarska I, Wheat AJ, Yaworski E, Zedalis W, Koteliansky V, Manoharan M, Vornlocher HP, MacLachlan I. RNAi-mediated gene silencing in non-human primates. Nature 2006; 441: 111-114
24. Arnold AS, Tang YL, Qian K, Shen L, Valencia V, Phillips MI, Zhang YC. Specific beta1-Adrenergic receptor silencing with small interfering RNA lowers high blood pressure and improves cardiac function in myocardial ischemia. J Hypertens 2007; 25: 197-205
25. Morrissey DV, Lockridge JA, Shaw L, Blanchard K, Jensen K, Breen W, Hartsough K, Machemer L, Radka S, Jadhav V, Vaish N, Zinnen S, Vargeese C, Bowman K, Shaffer CS, Jeffs LB, Judge A, MacLachlan I, Polisky B. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nat Biotechnol 2005; 23: 1002-1007
26. Abrams MT, Koser ML, Seitzer J, Williams SC, DiPietro MA, Wang W, Shaw AW, Mao X, Jadhav V, Davide JP, Burke PA, Sachs AB, Stirdivant SM, Sepp-Lorenzino L. Evaluation of efficacy, biodistribution, and inflammation for a potent siRNA nanoparticle: Effect of dexamethasone co-Treatment. Mol Ther 2010; 18: 171-180
27. Burchard J, Jackson AL, Malkov V, Needham RH, Tan Y, Bartz SR, Dai H, Sachs AB, Linsley PS. MicroRNA-like off-Target transcript regulation by siRNAs is species specific. RNA 2009; 15: 308-315
28. Tadin-Strapps M, Peterson LB, Cumiskey AM, Rosa RL, Mendoza VH, Castro-Perez J, Puig O, Zhang L, Strapps WR, Yendluri S, Andrews L, Pickering V, Rice J, Luo L, Chen Z, Tep S, Ason B, Somers EP, Sachs AB, Bartz SR, Tian J, Chin J, Hubbard BK, Wong KK, Mitnaul LJ. siRNA-induced liver ApoB knockdown lowers serum LDL-cholesterol in a mouse model with human-like serum lipids. J Lipid Res 2011; 52: 1084-1097
29. Shi B, Keough E, Matter A, Leander K, Young S, Carlini E, Sachs AB, Tao W, Abrams M, Howell B, Sepp-Lorenzino L. Biodistribution of small interfering RNA at the organ and cellular levels after lipid nanoparticle-mediated delivery. J Histochem Cytochem 2011; 59: 727-740
30. De Rosa ML. Cardio classics revisited-focus on the role of candesartan. Vasc Health Risk Manag 2010; 6: 1047-1063
31. Fuchs B, Breithaupt-Grogler K, Belz GG, Roll S, Malerczyk C, Herrmann V, Spahn-Langguth H, Mutschler E. Comparative pharmacodynamics and pharmacokinetics of candesartan and losartan in man. J PharmPharmacol 2000; 52: 1075-1083
32. Gleiter CH, Morike KE. Clinical pharmacokinetics of candesartan. Clin Pharmacokinet 2002; 41: 7-17
33. Khawaja Z, Wilcox CS. An overview of candesartan in clinical practice. Expert Rev Cardiovasc Ther 2011; 9: 975-982
34. Li L, Shen Y. Overcoming obstacles to develop effective and safe siRNA therapeutics. Expert Opin Biol Ther 2009; 9: 609-619
35. Gyurko R, Tran D, Phillips MI. Time course of inhibition of hypertension by antisense oligonucleotides targeted to AT1 angiotensin receptor mRNA in spontaneously hypertensive rats. Am J Hypertens 1997; 10(Pt 2), 56S-62S.
36. Wielbo D, Simon A, Phillips MI, Toffolo S. Inhibition of hypertension by peripheral administration of antisense oligodeoxynucleotides. Hypertension 1996; 28: 147-151
37. Zhang YC, Bui JD, Shen L, Phillips MI. Antisense inhibition of beta(1)-Adrenergic receptor mRNA in a single dose produces a profound and prolonged reduction in high blood pressure in spontaneously hypertensive rats. Circulation 2000; 101: 682-688
38. He J, Bian Y, Gao F, Li M, Qiu L, Wu W, Zhou H, Liu G, Xiao C. RNA interference targeting the ACE gene reduced blood pressure and improved myocardial remodelling in SHRs. Clin Sci (Lond) 2009; 116: 249-255
39. Tang X, Mohuczy D, Zhang YC, Kimura B, Galli SM, Phillips MI. Intravenous angiotensinogen antisense in AAV-based vector decreases hypertension. Am J Physiol 1999; 277 (Pt 2), H2392-H2399
40. Xiao CS, Zhang JL, Qiu L. The effects of shRNA targeting angiotensin II type 1 receptor on blood pressure and AT1R mRNA expression in spontaneously hypertensive rats. Zhonghua Xin Xue Guan Bing Za Zhi 2007; 35: 354-358
41. Lu P, Yuan L, Wang Y, Du Q, Sheng J. Effect of GPE-AGT nanoparticle shRNA transfection system mediated RNAi on early atherosclerotic lesion. Int J Clin Exp Pathol 2012; 5: 698-706
42. Peng JF, Kimura B, Fregly MJ, Phillips MI. Reduction of cold-induced hypertension by antisense oligodeoxynucleotides to angiotensinogen mRNA and AT1-receptor mRNA in brain and blood. Hypertension 1998; 31: 1317-1323
43. Makino N, Sugano M, Ohtsuka S, Sawada S, Hata T. Chronic antisense therapy for angiotensinogen on cardiac hypertrophy in spontaneously hypertensive rats. Cardiovasc Res 1999; 44: 543-548
44. Zhou H, Bian YF, Li ML, Gao F, Xiao CS. Effects of RNA interference targeting angiotensin 1 receptor and angiotensin-converting enzyme on blood pressure and myocardial remodeling in spontaneous hypertensive rats. Zhonghua Xin Xue Guan Bing Za Zhi 2010; 38: 60-66
45. Muiesan ML, Salvetti M, Rizzoni D, Paini A, Agabiti-Rosei C, Aggiusti C, Agabiti Rosei E. Resistant hypertension and target organ damage. Hypertens Res 2013; 36: 485-491
46. Conrad CH, Brooks WW, Hayes JA, Sen S, Robinson KG, Bing OH. Myocardial fibrosis and stiffness with hypertrophy and heart failure in the spontaneously hypertensive rat. Circulation 1995; 91: 161-170
47. Galuppo P, Bauersachs J. Mineralocorticoid receptor activation in myocardial infarction and failure: Recent advances. Eur J Clin Invest 2012; 42: 1112-1120
48. Zwadlo C, Bauersachs J. Mineralocorticoid receptor antagonists for therapy of coronary artery disease and related complications. Curr Opin Pharmacol 2013; 13: 280-286
49. DiNicolantonio R, Doyle AE. Comparison of the actions of the angiotensin-converting enzyme inhibitors enalapril and S-9490-3 in sodium-deplete and sodium-replete spontaneously hypertensive rats. J Cardiovasc Pharmacol 1985; 7: 937-942
50. Vincent ME, Swanson BN, Shepley K, Ferguson RK. Hemodynamic and humoral responses to enalapril and nifedipine in the rat. Clin Exp Hypertens A 1984; 6: 1485-1497
51. Jayaraman M, Ansell SM, Mui BL, Tam YK, Chen J, Du X, Butler D, Eltepu L, Matsuda S, Narayanannair JK, Rajeev KG, Hafez IM, Akinc A, Maier MA, Tracy MA, Cullis PR, Madden TD, Manoharan M, Hope MJ. Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo. Angew Chem Int Ed Engl 2012; 51: 8529-8533
52. Novobrantseva TI, Borodovsky A, Wong J, Klebanov B, Zafari M, Yucius K, Querbes W, Ge P, Ruda VM, Milstein S, Speciner L, Duncan R, Barros S, Basha G, Cullis P, Akinc A, Donahoe JS, Narayanannair Jayaprakash K, Jayaraman M, Bogorad RL, Love K, Whitehead K, Levins C, Manoharan M, Swirski FK, Weissleder R, Langer R, Anderson DG, de Fougerolles A, Nahrendorf M, Koteliansky V. Systemic RNAi-mediated gene silencing in nonhuman primate and rodent myeloid cells. Mol Ther Nucleic Acids 2013; 1: E4
53. Ason B, Castro-Perez J, Tep S, Stefanni A, Tadin-Strapps M, Roddy T, Hankemeier T, Hubbard B, Sachs AB, Michael Flanagan W, Kuklin NA, Mitnaul LJ. ApoB siRNAinduced liver steatosis is resistant to clearance by the loss of fatty acid transport protein 5 (Fatp5). Lipids 2011; 46: 991-1003
54. Tep S, Mihaila R, Freeman A, Pickering V, Huynh F, Tadin-Strapps M, Stracks A, Hubbard B, Caldwell J, Flanagan WM, Kuklin NA, Ason B. Rescue of Mtp siRNAinduced hepatic steatosis by DGAT2 siRNA silencing. J Lipid Res 2012; 53: 859-867
55. Zhou J, Neff CP, Liu X, Zhang J, Li H, Smith DD, Swiderski P, Aboellail T, Huang Y, Du Q, Liang Z, Peng L, Akkina R, Rossi JJ. Systemic administration of combinatorial dsiRNAs via nanoparticles efficiently suppresses HIV-1 infection in humanized mice. Mol Ther 2011; 19: 2228-2238