Recombinant adeno-associated virus-mediated delivery of antisense angiotensin ii receptor 1 gene attenuates hypertension development

Recombinant adeno-associated virus-mediated delivery of antisense angiotensin ii receptor 1 gene attenuates hypertension development

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ABSTRACT AIM: The renin-angiotensin system plays a crucial role in the development and establishment of hypertension, and the pharmacological blockade of the system results in a reduction in blood pressure. In the present study, we investigated whether the effects of a novel, double-stranded, recombinant adeno-associated virus vector (rAAV)-mediated antisense angiotensin II receptor 1 (AT1R) gene efficiently prevents the development of hypertension induced by a high-salt diet in adult, male Sprague-Dawley (SD) rats. METHODS: A rAAV was prepared with a cassette containing a cytomegaloviruspromoter and partial cDNA (660 base pairs) for the AT1R inserted in the antisense direction (rAAV-AT1-AS). A single tail vein injection of the rAAV-AT1-AS or rAAV-GFP (green fluorescent protein, a reporter gene) was performed in adult, male SD rats. Two weeks after injection, the animals were fed a diet containing 8% NaCl, and the systolic blood pressure was measured weekly using the tail-cuff method for 12 weeks. RESULTS: The high-salt diet induced a significant rise in systolic blood pressure in the rAAV-GFP-treated animals; however, the rAAV-AT1-AS treatment attenuated the rise in blood pressure (142.7±4.5 mmHg _vs_ 117±3.8 mmHg, _P_<0.01), and the hypotensive effect was maintained until the experiments ended at 12 weeks. In the rAAV-GFP-treated animals AT1 was overexpressed in various tissues, especially in the aorta and kidney at mRNA levels; in contrast, rAAV-AT1-AS treatment markedly attenuated AT1 expression. Further more, rAAV-AT1-AS treatment prevented target organ damages from hypertension, including cardiac dysfunction and renal injury compared to the rAAV-GFP group. CONCLUSION: These results suggest that rAAV-mediated anti-AT1 delivery attenuates the development of hypertension and protects against renal injury and cardiac remodeling. SIMILAR CONTENT BEING VIEWED BY OTHERS ENHANCEMENT OF ANGIOTENSIN II TYPE 1 RECEPTOR-ASSOCIATED PROTEIN IN THE PARAVENTRICULAR NUCLEUS SUPPRESSES ANGIOTENSIN II-DEPENDENT HYPERTENSION Article 26 October 2023 TRANSGENIC RAT WITH UBIQUITOUS EXPRESSION OF ANGIOTENSIN-(1-7)-PRODUCING FUSION PROTEIN: A NEW TOOL TO STUDY THE ROLE OF PROTECTIVE ARM OF THE RENIN-ANGIOTENSIN SYSTEM IN THE PATHOPHYSIOLOGY OF CARDIO-RENAL DISEASES Article Open access 13 November 2024 RENALASE IMPROVES PRESSURE OVERLOAD-INDUCED HEART FAILURE IN RATS BY REGULATING EXTRACELLULAR SIGNAL-REGULATED PROTEIN KINASE 1/2 SIGNALING Article 08 January 2021 ARTICLE PDF REFERENCES * Folkow B . Critical review of studies on salt and hypertension. _Clin Exp Hypertens A_ 1992; 14: 1–14. CAS  PubMed  Google Scholar  * Haddy FJ, Pamnani MB . Role of dietary salt in hypertension. _J Am Coll Nutr_ 1995; 14: 428–38. Article  CAS  Google Scholar  * Muntzel M, Druecke T . A comprehensive review of the salt and blood pressure relationship. _Am J Hypertens_ 1992; 5: 1–42. Article  Google Scholar  * Weinberger MH . Sodium sensitivity and blood pressure. _Curr Opin Nephrol Hypertens_ 1993; 2: 935–9. Article  CAS  Google Scholar  * Reid I . The renin-angiotensin system: physiology, pathophysiology, and pharmacology. _Advan Physiol Edu_ 1998; 275: 236–45. Article  Google Scholar  * Alderman, MH, Madhavan, S, Ooi, WL, Cohen, H, Sealy, JE, Laragh, JH Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension. _New Engl J Med_ 1991; 324: 1098–104. Article  CAS  Google Scholar  * Nickenig G, Strehlow K, Roeling J, Zolk O, Knorr A, Böhm M . Salt induces vascular AT1 receptor overexpression in vitro and in vivo. _Hypertension_ 1998; 31: 1272–7. Article  CAS  Google Scholar  * Gonzalez M, Lobos L, Castillo F, Gastillo F, Gallequillos L, Lopez NC, Michea L . High-salt diet inhibits expression of angiotensin type 2 receptor in resistance arteries. _Hypertension_ 2005; 45: 853–9. Article  CAS  Google Scholar  * Phillips MI . Gene therapy for hypertension. _Hypertension_ 2001; 38: 543–8. Article  CAS  Google Scholar  * Iyer SN, Lu D, Katovich MJ, Raizada MK . Chronic control of high blood pressure in the spontaneously hypertensive rat by delivery of angiotensin type 1 receptor antisense. _Proc Natl Acad Sci USA_ 1996; 93: 9960–5. Article  CAS  Google Scholar  * Gyurko R, Wielbo D, Phillips MI . Antisense inhibition of AT1 receptor mRNA and angiotensinogen mRNA in the brain of spontaneously hypertensive rats reduces hypertension of neurogenic origin. _Regul Pept_ 1993; 49: 167–74. Article  CAS  Google Scholar  * Phillips MI, Wielbo D, Gyurko R . Antisense inhibition of hypertension: a new strategy for renin-angiotensin candidate genes. _Kidney Int_ 1994; 46: 1554–6. Article  CAS  Google Scholar  * Wielbo D, Sernia C, Gyurko R, Phillips MI . Antisense inhibition of hypertension in the spontaneously hypertensive rat. _Hypertension_ 1995; 25: 314–9. Article  CAS  Google Scholar  * Wang X, Sun Z, Cade R . Prolonged attenuation of cold-induced hypertension by adenoviral delivery of renin antisense. _Kidney Int_ 2005; 68: 680–7. Article  CAS  Google Scholar  * 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: 1317–23. Article  CAS  Google Scholar  * Kimura B, Mohuczy D, Tang X, Phillips MI . Attenuation of hypertension and heart hypertrophy by adeno-associated virus delivering angiotensinogen antisense. _Hypertension_ 2001; 37: 376–80. Article  CAS  Google Scholar  * Wang H, Katovich MJ, Gelband CH . Sustained inhibition of angiotensin I-converting enzyme (ACE) expression and long-term antihypertensive action by virally mediated delivery of ACE antisense cDNA. _Circ Res_ 1999; 85: 614–22. Article  CAS  Google Scholar  * Muzyczka N, McLaughin S . Use of adeno-associated virus as a mammalian transduction vector. In: Gluzman Y, Hughes, SH _Current communications in molecular biology: viral vectors_. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 1988. p 39–44. Google Scholar  * Muzyczka N . Use of adeno-associated virus as a general transduction vector for mammalian cells. In: _Current topics in microbiology and immunology_. Berlin, Germany: Springer-Verlag; 1992. p 97–129. Google Scholar  * Samulski RJ, Zhu X, Xiao X, Brook JD, Housman DE, Estien N, _et al_. Targeted integration of adeno-associated virus (AAV) into human chromosome 19. _EMBO J_ 1991; 10: 3941–50. Article  CAS  Google Scholar  * Xiao X, Li J, Samulski RJ . Production of high-titer recombinant adeno-associated virus vectors in the absence of helper adenovirus. _J Virol_ 1998; 72: 2224–32. * Wang Z, Ma HI, Li J, Sun L, Zhang J, Xiao X . Rapid and highly efficient transduction by double-stranded adeno-associated virus vectors in vitro and in vivo. _Gene Ther_ 2003; 10: 2105–11. Article  CAS  Google Scholar  * Wang T, Li H, Zhao C, Chen C, Li J, Chao J, _et al_. Recombinant adeno-associated virus-mediated kallikrein gene therapy reduces hypertension and attenuates its cardiovascular injuries. _Gene Ther_ 2004; 11: 1342–50. Article  CAS  Google Scholar  * Auricchio A, Hildinger M, O'Connor E, Gao G, Wilson JM . Isolation of highly infectious and pure adeno-associated virus type 2 vectors with a single-step gravity-flow column. _Hum Gene Ther_ 2001; 12: 71–6. Article  CAS  Google Scholar  * Dobrzynski E, Wang C, Chao J, Chao L . Adrenomedullin gene delivery attenuates hypertension, cardiac remodeling, and renal injury in deoxycorticosterone acetate-salt hypertensive rats. _Hypertension_ 2000; 36: 995–1001. Article  CAS  Google Scholar  * Cindy W, Eric D, Julie C, Lee C . Adrenomedullin gene delivery attenuates renal damage and cardiac hypertrophy in Goldblatt hypertensive rats. _Am J Physiol Ren Physiol_ 2001; 280: F964–71. Article  Google Scholar  * Yan Z, Zhang Y, Duan D, Englhardt J . From the cover: trans-splicing vectors expand the utility of adeno-associated virus for gene therapy. _Proc Natl Acad Sci USA_ 2000; 97: 6716–21. Article  CAS  Google Scholar  * Yang J, Zhou W, Zhang Y . Concatamerization of adeno-associated virus circular genomes occurs through intermolecular recombination. _J Virol_ 1999; 73, 9468–77. * Michael H . Alderman. Salt, blood pressure and health: a cautionary tale. _Int J Epidemiol_ 2002; 31: 311–6. Article  Google Scholar  * Intersalt. An international study of electrolyte excretion and blood pressure: results for 24 h urinary sodium and potassium excretion: Intersalt Cooperative Research Group. _Brit Med J_ 1988; 297: 319–28. * Mancilha-Carvalho, JJ, Souzae Silva, NA . The Yanomami Indians in the INTERSALT Study. _Arq Bras Cardiol_ 2003; 80: 295–300. Article  Google Scholar  * Sechi LA, Griffin CA, Giacchetti G, Valentin JP, Llorens-Cortes C, Corvol P, _et al_. Tissue-specific regulation of type 1 angiotensin II receptor mRNA levels in the rat. _Hypertension_ 1996; 28: 403–8. Article  CAS  Google Scholar  * Du Cailar, G, Ribstein J, Mimran A . Dietary sodium and target organ damage in essential hypertension. _Am J Hypertens_ 2002; 15: 222–9. Article  CAS  Google Scholar  * de Wardener HE, MacGregor GA . Harmful effects of dietary salt in addition to hypertension. _J Hum Hypertens_ 2002; 16: 213–23. Article  CAS  Google Scholar  * Safar ME, Thuilliez C, Richard V, Benetos A . Pressure-independent contribution of sodium to large artery structure and function in hypertension. _Cardiovasc Res_ 2000; 46: 269–76. Article  CAS  Google Scholar  * Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beervers G, de Faire U, _et al_. Cardiovascular morbidity and mortality in the Losartan Intervention for endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. _Lancet_ 2002; 359: 995–1003. Article  CAS  Google Scholar  * Kjeldsen SE, Dahlof B, Devereux RB, Julius S, Aurup P, Edelman J, _et al_. Effects of losartan on cardiovascular morbidity and mortality in patients with isolated systolic hypertension and left ventricular hypertrophy: a Losartan Intervention for Endpoint Reduction (LIFE) substudy. _JAMA_ 2002; 288: 1491–8. Article  CAS  Google Scholar  * Galli SM, Phillips MI . Angiotensin II AT(1A) receptor antisense lowers blood pressure in acute 2-kidney, 1-clip hypertension. _Hypertension_ 2001; 38: 674–8. Article  CAS  Google Scholar  * Phillips MI, Mohuczy-Dominiak D, Coffey M . Prolonged reduction of high blood pressure with an in vivo, nonpathogenic, adeno-associated viral vector delivery of AT1-R mRNA antisense. _Hypertension_ 1997; 29: 374–80. Article  CAS  Google Scholar  * Phillips MI . Antisense inhibition and adeno-associated viral vector delivery for reducing hypertension. _Hypertension_ 1997; 29: 177–87. Article  CAS  Google Scholar  * Katovich MJ, Gelband CH, Reaves P . Reversal of hypertension by angiotensin II type 1 receptor antisense gene therapy in the adult SHR. _Am J Physiol_ 1999; 277: H1260–4. CAS  PubMed  Google Scholar  * Reaves PY, Beck CR, Wang HW . Endothelial-independent prevention of high blood pressure in L-NAME-treated rats by angiotensin II type I receptor antisense gene therapy. _Exp Physiol_ 2003; 88: 467–73. Article  CAS  Google Scholar  * Pachori AS, Numan MT, Ferrario CM, Diz DM, Raizada MK, Katovich MJ . Blood pressure-independent attenuation of cardiac hypertrophy by AT(1)R-AS gene therapy. _Hypertension_ 2002; 39: 969–75. Article  CAS  Google Scholar  Download references AUTHOR INFORMATION Author notes * Xu-guang Li and Jiang-tao Yan: These authors contributed equally to this study. AUTHORS AND AFFILIATIONS * Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China Xu-guang Li, Jiang-tao Yan, Xi-zheng Xu, Jia-ning Wang, Li-ming Cheng, Tao Wang, Ping Zuo & Dao-wen Wang Authors * Xu-guang Li View author publications You can also search for this author inPubMed Google Scholar * Jiang-tao Yan View author publications You can also search for this author inPubMed Google Scholar * Xi-zheng Xu View author publications You can also search for this author inPubMed Google Scholar * Jia-ning Wang View author publications You can also search for this author inPubMed Google Scholar * Li-ming Cheng View author publications You can also search for this author inPubMed Google Scholar * Tao Wang View author publications You can also search for this author inPubMed Google Scholar * Ping Zuo View author publications You can also search for this author inPubMed Google Scholar * Dao-wen Wang View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Dao-wen Wang. ADDITIONAL INFORMATION This work was supported by grants from the National 863 Plan project (No 2004AA-217060), the National Basic Research “973” Program (No 2006CB503801), and the National Education Ministration project (No 20040487079). RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Li, Xg., Yan, Jt., Xu, Xz. _et al._ Recombinant adeno-associated virus-mediated delivery of antisense angiotensin II receptor 1 gene attenuates hypertension development. _Acta Pharmacol Sin_ 28, 1737–1745 (2007). https://doi.org/10.1111/j.1745-7254.2007.00676.x Download citation * Received: 11 June 2007 * Accepted: 24 June 2007 * Issue Date: 01 November 2007 * DOI: https://doi.org/10.1111/j.1745-7254.2007.00676.x SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * hypertension * gene therapy * angiotensin II receptor 1 * antisense * double-stranded recombinant adeno-associated virus vector

ABSTRACT AIM: The renin-angiotensin system plays a crucial role in the development and establishment of hypertension, and the pharmacological blockade of the system results in a reduction in


blood pressure. In the present study, we investigated whether the effects of a novel, double-stranded, recombinant adeno-associated virus vector (rAAV)-mediated antisense angiotensin II


receptor 1 (AT1R) gene efficiently prevents the development of hypertension induced by a high-salt diet in adult, male Sprague-Dawley (SD) rats. METHODS: A rAAV was prepared with a cassette


containing a cytomegaloviruspromoter and partial cDNA (660 base pairs) for the AT1R inserted in the antisense direction (rAAV-AT1-AS). A single tail vein injection of the rAAV-AT1-AS or


rAAV-GFP (green fluorescent protein, a reporter gene) was performed in adult, male SD rats. Two weeks after injection, the animals were fed a diet containing 8% NaCl, and the systolic blood


pressure was measured weekly using the tail-cuff method for 12 weeks. RESULTS: The high-salt diet induced a significant rise in systolic blood pressure in the rAAV-GFP-treated animals;


however, the rAAV-AT1-AS treatment attenuated the rise in blood pressure (142.7±4.5 mmHg _vs_ 117±3.8 mmHg, _P_<0.01), and the hypotensive effect was maintained until the experiments


ended at 12 weeks. In the rAAV-GFP-treated animals AT1 was overexpressed in various tissues, especially in the aorta and kidney at mRNA levels; in contrast, rAAV-AT1-AS treatment markedly


attenuated AT1 expression. Further more, rAAV-AT1-AS treatment prevented target organ damages from hypertension, including cardiac dysfunction and renal injury compared to the rAAV-GFP


group. CONCLUSION: These results suggest that rAAV-mediated anti-AT1 delivery attenuates the development of hypertension and protects against renal injury and cardiac remodeling. SIMILAR


CONTENT BEING VIEWED BY OTHERS ENHANCEMENT OF ANGIOTENSIN II TYPE 1 RECEPTOR-ASSOCIATED PROTEIN IN THE PARAVENTRICULAR NUCLEUS SUPPRESSES ANGIOTENSIN II-DEPENDENT HYPERTENSION Article 26


October 2023 TRANSGENIC RAT WITH UBIQUITOUS EXPRESSION OF ANGIOTENSIN-(1-7)-PRODUCING FUSION PROTEIN: A NEW TOOL TO STUDY THE ROLE OF PROTECTIVE ARM OF THE RENIN-ANGIOTENSIN SYSTEM IN THE


PATHOPHYSIOLOGY OF CARDIO-RENAL DISEASES Article Open access 13 November 2024 RENALASE IMPROVES PRESSURE OVERLOAD-INDUCED HEART FAILURE IN RATS BY REGULATING EXTRACELLULAR SIGNAL-REGULATED


PROTEIN KINASE 1/2 SIGNALING Article 08 January 2021 ARTICLE PDF REFERENCES * Folkow B . Critical review of studies on salt and hypertension. _Clin Exp Hypertens A_ 1992; 14: 1–14. CAS 


PubMed  Google Scholar  * Haddy FJ, Pamnani MB . Role of dietary salt in hypertension. _J Am Coll Nutr_ 1995; 14: 428–38. Article  CAS  Google Scholar  * Muntzel M, Druecke T . A


comprehensive review of the salt and blood pressure relationship. _Am J Hypertens_ 1992; 5: 1–42. Article  Google Scholar  * Weinberger MH . Sodium sensitivity and blood pressure. _Curr Opin


Nephrol Hypertens_ 1993; 2: 935–9. Article  CAS  Google Scholar  * Reid I . The renin-angiotensin system: physiology, pathophysiology, and pharmacology. _Advan Physiol Edu_ 1998; 275:


236–45. Article  Google Scholar  * Alderman, MH, Madhavan, S, Ooi, WL, Cohen, H, Sealy, JE, Laragh, JH Association of the renin-sodium profile with the risk of myocardial infarction in


patients with hypertension. _New Engl J Med_ 1991; 324: 1098–104. Article  CAS  Google Scholar  * Nickenig G, Strehlow K, Roeling J, Zolk O, Knorr A, Böhm M . Salt induces vascular AT1


receptor overexpression in vitro and in vivo. _Hypertension_ 1998; 31: 1272–7. Article  CAS  Google Scholar  * Gonzalez M, Lobos L, Castillo F, Gastillo F, Gallequillos L, Lopez NC, Michea L


. High-salt diet inhibits expression of angiotensin type 2 receptor in resistance arteries. _Hypertension_ 2005; 45: 853–9. Article  CAS  Google Scholar  * Phillips MI . Gene therapy for


hypertension. _Hypertension_ 2001; 38: 543–8. Article  CAS  Google Scholar  * Iyer SN, Lu D, Katovich MJ, Raizada MK . Chronic control of high blood pressure in the spontaneously


hypertensive rat by delivery of angiotensin type 1 receptor antisense. _Proc Natl Acad Sci USA_ 1996; 93: 9960–5. Article  CAS  Google Scholar  * Gyurko R, Wielbo D, Phillips MI . Antisense


inhibition of AT1 receptor mRNA and angiotensinogen mRNA in the brain of spontaneously hypertensive rats reduces hypertension of neurogenic origin. _Regul Pept_ 1993; 49: 167–74. Article 


CAS  Google Scholar  * Phillips MI, Wielbo D, Gyurko R . Antisense inhibition of hypertension: a new strategy for renin-angiotensin candidate genes. _Kidney Int_ 1994; 46: 1554–6. Article 


CAS  Google Scholar  * Wielbo D, Sernia C, Gyurko R, Phillips MI . Antisense inhibition of hypertension in the spontaneously hypertensive rat. _Hypertension_ 1995; 25: 314–9. Article  CAS 


Google Scholar  * Wang X, Sun Z, Cade R . Prolonged attenuation of cold-induced hypertension by adenoviral delivery of renin antisense. _Kidney Int_ 2005; 68: 680–7. Article  CAS  Google


Scholar  * 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: 1317–23. Article  CAS  Google Scholar  * Kimura B, Mohuczy D, Tang X, Phillips MI . Attenuation of hypertension and heart hypertrophy by adeno-associated


virus delivering angiotensinogen antisense. _Hypertension_ 2001; 37: 376–80. Article  CAS  Google Scholar  * Wang H, Katovich MJ, Gelband CH . Sustained inhibition of angiotensin


I-converting enzyme (ACE) expression and long-term antihypertensive action by virally mediated delivery of ACE antisense cDNA. _Circ Res_ 1999; 85: 614–22. Article  CAS  Google Scholar  *


Muzyczka N, McLaughin S . Use of adeno-associated virus as a mammalian transduction vector. In: Gluzman Y, Hughes, SH _Current communications in molecular biology: viral vectors_. Cold


Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 1988. p 39–44. Google Scholar  * Muzyczka N . Use of adeno-associated virus as a general transduction vector for mammalian cells. In:


_Current topics in microbiology and immunology_. Berlin, Germany: Springer-Verlag; 1992. p 97–129. Google Scholar  * Samulski RJ, Zhu X, Xiao X, Brook JD, Housman DE, Estien N, _et al_.


Targeted integration of adeno-associated virus (AAV) into human chromosome 19. _EMBO J_ 1991; 10: 3941–50. Article  CAS  Google Scholar  * Xiao X, Li J, Samulski RJ . Production of


high-titer recombinant adeno-associated virus vectors in the absence of helper adenovirus. _J Virol_ 1998; 72: 2224–32. * Wang Z, Ma HI, Li J, Sun L, Zhang J, Xiao X . Rapid and highly


efficient transduction by double-stranded adeno-associated virus vectors in vitro and in vivo. _Gene Ther_ 2003; 10: 2105–11. Article  CAS  Google Scholar  * Wang T, Li H, Zhao C, Chen C, Li


J, Chao J, _et al_. Recombinant adeno-associated virus-mediated kallikrein gene therapy reduces hypertension and attenuates its cardiovascular injuries. _Gene Ther_ 2004; 11: 1342–50.


Article  CAS  Google Scholar  * Auricchio A, Hildinger M, O'Connor E, Gao G, Wilson JM . Isolation of highly infectious and pure adeno-associated virus type 2 vectors with a single-step


gravity-flow column. _Hum Gene Ther_ 2001; 12: 71–6. Article  CAS  Google Scholar  * Dobrzynski E, Wang C, Chao J, Chao L . Adrenomedullin gene delivery attenuates hypertension, cardiac


remodeling, and renal injury in deoxycorticosterone acetate-salt hypertensive rats. _Hypertension_ 2000; 36: 995–1001. Article  CAS  Google Scholar  * Cindy W, Eric D, Julie C, Lee C .


Adrenomedullin gene delivery attenuates renal damage and cardiac hypertrophy in Goldblatt hypertensive rats. _Am J Physiol Ren Physiol_ 2001; 280: F964–71. Article  Google Scholar  * Yan Z,


Zhang Y, Duan D, Englhardt J . From the cover: trans-splicing vectors expand the utility of adeno-associated virus for gene therapy. _Proc Natl Acad Sci USA_ 2000; 97: 6716–21. Article  CAS


  Google Scholar  * Yang J, Zhou W, Zhang Y . Concatamerization of adeno-associated virus circular genomes occurs through intermolecular recombination. _J Virol_ 1999; 73, 9468–77. * Michael


H . Alderman. Salt, blood pressure and health: a cautionary tale. _Int J Epidemiol_ 2002; 31: 311–6. Article  Google Scholar  * Intersalt. An international study of electrolyte excretion


and blood pressure: results for 24 h urinary sodium and potassium excretion: Intersalt Cooperative Research Group. _Brit Med J_ 1988; 297: 319–28. * Mancilha-Carvalho, JJ, Souzae Silva, NA .


The Yanomami Indians in the INTERSALT Study. _Arq Bras Cardiol_ 2003; 80: 295–300. Article  Google Scholar  * Sechi LA, Griffin CA, Giacchetti G, Valentin JP, Llorens-Cortes C, Corvol P,


_et al_. Tissue-specific regulation of type 1 angiotensin II receptor mRNA levels in the rat. _Hypertension_ 1996; 28: 403–8. Article  CAS  Google Scholar  * Du Cailar, G, Ribstein J, Mimran


A . Dietary sodium and target organ damage in essential hypertension. _Am J Hypertens_ 2002; 15: 222–9. Article  CAS  Google Scholar  * de Wardener HE, MacGregor GA . Harmful effects of


dietary salt in addition to hypertension. _J Hum Hypertens_ 2002; 16: 213–23. Article  CAS  Google Scholar  * Safar ME, Thuilliez C, Richard V, Benetos A . Pressure-independent contribution


of sodium to large artery structure and function in hypertension. _Cardiovasc Res_ 2000; 46: 269–76. Article  CAS  Google Scholar  * Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beervers G,


de Faire U, _et al_. Cardiovascular morbidity and mortality in the Losartan Intervention for endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. _Lancet_


2002; 359: 995–1003. Article  CAS  Google Scholar  * Kjeldsen SE, Dahlof B, Devereux RB, Julius S, Aurup P, Edelman J, _et al_. Effects of losartan on cardiovascular morbidity and mortality


in patients with isolated systolic hypertension and left ventricular hypertrophy: a Losartan Intervention for Endpoint Reduction (LIFE) substudy. _JAMA_ 2002; 288: 1491–8. Article  CAS 


Google Scholar  * Galli SM, Phillips MI . Angiotensin II AT(1A) receptor antisense lowers blood pressure in acute 2-kidney, 1-clip hypertension. _Hypertension_ 2001; 38: 674–8. Article  CAS


  Google Scholar  * Phillips MI, Mohuczy-Dominiak D, Coffey M . Prolonged reduction of high blood pressure with an in vivo, nonpathogenic, adeno-associated viral vector delivery of AT1-R


mRNA antisense. _Hypertension_ 1997; 29: 374–80. Article  CAS  Google Scholar  * Phillips MI . Antisense inhibition and adeno-associated viral vector delivery for reducing hypertension.


_Hypertension_ 1997; 29: 177–87. Article  CAS  Google Scholar  * Katovich MJ, Gelband CH, Reaves P . Reversal of hypertension by angiotensin II type 1 receptor antisense gene therapy in the


adult SHR. _Am J Physiol_ 1999; 277: H1260–4. CAS  PubMed  Google Scholar  * Reaves PY, Beck CR, Wang HW . Endothelial-independent prevention of high blood pressure in L-NAME-treated rats by


angiotensin II type I receptor antisense gene therapy. _Exp Physiol_ 2003; 88: 467–73. Article  CAS  Google Scholar  * Pachori AS, Numan MT, Ferrario CM, Diz DM, Raizada MK, Katovich MJ .


Blood pressure-independent attenuation of cardiac hypertrophy by AT(1)R-AS gene therapy. _Hypertension_ 2002; 39: 969–75. Article  CAS  Google Scholar  Download references AUTHOR INFORMATION


Author notes * Xu-guang Li and Jiang-tao Yan: These authors contributed equally to this study. AUTHORS AND AFFILIATIONS * Institute of Hypertension and Department of Internal Medicine,


Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China Xu-guang Li, Jiang-tao Yan, Xi-zheng Xu, Jia-ning Wang, Li-ming Cheng, Tao Wang, 


Ping Zuo & Dao-wen Wang Authors * Xu-guang Li View author publications You can also search for this author inPubMed Google Scholar * Jiang-tao Yan View author publications You can also


search for this author inPubMed Google Scholar * Xi-zheng Xu View author publications You can also search for this author inPubMed Google Scholar * Jia-ning Wang View author publications You


can also search for this author inPubMed Google Scholar * Li-ming Cheng View author publications You can also search for this author inPubMed Google Scholar * Tao Wang View author


publications You can also search for this author inPubMed Google Scholar * Ping Zuo View author publications You can also search for this author inPubMed Google Scholar * Dao-wen Wang View


author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Dao-wen Wang. ADDITIONAL INFORMATION This work was supported by grants


from the National 863 Plan project (No 2004AA-217060), the National Basic Research “973” Program (No 2006CB503801), and the National Education Ministration project (No 20040487079). RIGHTS


AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Li, Xg., Yan, Jt., Xu, Xz. _et al._ Recombinant adeno-associated virus-mediated delivery of antisense


angiotensin II receptor 1 gene attenuates hypertension development. _Acta Pharmacol Sin_ 28, 1737–1745 (2007). https://doi.org/10.1111/j.1745-7254.2007.00676.x Download citation * Received:


11 June 2007 * Accepted: 24 June 2007 * Issue Date: 01 November 2007 * DOI: https://doi.org/10.1111/j.1745-7254.2007.00676.x SHARE THIS ARTICLE Anyone you share the following link with will


be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt


content-sharing initiative KEYWORDS * hypertension * gene therapy * angiotensin II receptor 1 * antisense * double-stranded recombinant adeno-associated virus vector