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

<正> Aim:The renin-angiotensin system plays a crucial role in the development andestablishment of hypertension,and the pharmacological blockade of the systemresults in a reduction in blood pressure.In the present study,we investigatedwhether the effects of a novel,double-stranded,recombinant adeno-associatedvirus vector （rAAV）-mediated antisense angiotensin Ⅱ receptor 1 （AT1R） geneefficiently prevents the development of hypertension induced by a high-salt dietin adult,male Sprague-Dawley （SD） rats.Methods:A rAAV was prepared with acassette containing a cytomegalovirus promoter and partial cDNA （660 base pairs）for the AT1R inserted in the antisense direction （rAAV-AT1-AS）.A single tail veininjection of the rAAV-AT1-AS or rAAV-GFP （green fluorescent protein,a reportergene） was performed in adult,male SD rats.Two weeks after injection,the animalswere fed a diet containing 8% NaCl,and the systolic blood pressure was measuredweekly using the tail-cuff method for 12 weeks.Results:The high-salt dietinduced a significant rise in systolic blood pressure in the rAAV-GFP-treatedanimals;however,the rAAV-AT1-AS treatment attenuated the rise in blood pres-sure （142.7±4.5 mmHg vs 117±3.8 mmHg,P<0.01）,and the hypotensive effect wasmaintained until the experiments ended at 12 weeks.In the rAAV-GFP-treatedanimals AT1 was overexpressed in various tissues,especially in the aorta andkidney at mRNA levels;in contrast,rAAV-AT1-AS treatment markedly attenuatedAT1 expression.Furthermore,rAAV-AT1-AS treatment prevented target organdamages from hypertension,including cardiac dysfunction and renal injury com-pared to the rAAV-GFP group.Conclusion:These results suggest that rAAV-mediated anti-AT1 delivery attenuates the development of hypertension and pro-tects against renal injury and cardiac remodeling.