Attenuation of Hypertension and Heart Hypertrophy by Adeno-Associated Virus Delivering Angiotensinogen Antisense

Abstract

Angiotensinogen (AGT), one of the major components in the renin-angiotensin system, has been linked to hypertension in humans and animals. We have previously systemically administered antisense oligonucleotides and plasmid vectors with DNA that targeted AGT and attenuated hypertension in spontaneously hypertensive rats. The aim of the present study was to prolong the effect of antisense treatment by the use of a recombinant adeno-associated viral (rAAV) vector targeted to AGT. Using a model of lifelong hypertension in which 5-day-old spontaneously hypertensive rats are treated, a single intracardiac injection of rAAV-AGT-antisense (rAAV-AGT-AS) delayed the onset of hypertension for 91 days and significantly attenuated hypertension in adulthood for up to 6 months. Systolic blood pressure was always lower, by up to 23 mm Hg in the AS-treated group. The vector was stable and expressed a reporter gene in liver, kidney, and heart. The rAAV-AGT-AS treatment significantly decreased left ventricular hypertrophy ( P =0.01) and also lowered levels of AGT in the liver (2.78±0.61 μg/g tissue versus 5.23±0.41 μg/g tissue for the sense-treated group, P <0.01). Measurement of liver transaminases showed no evidence for liver toxicity. We conclude that rAAV-AGT-AS offers a safe, stable approach for gene therapy of hypertension.