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.
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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).
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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
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DOI: https://doi.org/10.1111/j.1745-7254.2007.00676.x