Recombinant adeno-associated virus-mediated delivery of antisense angiotensin II receptor 1 gene attenuates hypertension development.
OBJECTIVE
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 cytomegalovirus promoter 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. Furthermore, rAAV-AT1-AS treatment prevented target organ damages from hypertension, including cardiac dysfunction and renal injury compared to the rAAV-GFP group.


CONCLUSIONS
These results suggest that rAAVmediated anti-AT1 delivery attenuates the development of hypertension and protects against renal injury and cardiac remodeling.
Li
Xu-guang
XG
Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Yan
Jiang-tao
JT
Xu
Xi-zheng
XZ
Wang
Jia-ning
JN
Cheng
Li-ming
LM
Wang
Tao
T
Zuo
Ping
P
Wang
Dao-wen
DW
D000419:Albuminuria / Q000517:prevention & control; D000818:Animals; D006332:Cardiomegaly; D016373:DNA, Antisense / Q000378:metabolism / Q000627:therapeutic use*; D000229:Dependovirus / Q000235:genetics*; D005355:Fibrosis / Q000517:prevention & control; D015316:Genetic Therapy; D005822:Genetic Vectors; D006321:Heart / Q000503:physiopathology; D006973:Hypertension / Q000139:chemically induced / Q000628:therapy*; D008297:Male; D009206:Myocardium / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics*; D012965:Sodium Chloride / Q000008:administration & dosage / Q000009:adverse effects
D016373:DNA, Antisense; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D012965:Sodium Chloride