Nanoparticle-mediated RNA interference of angiotensinogen decreases blood pressure and improves myocardial remodeling in spontaneously hypertensive rats

Angiotensinogen (AGT) has been shown to have a role in cardiac hypertrophy, while depletion of the AGT gene in spontaneously hypertensive rats (SHR) has not been investigated. The present study investigated the effect of AGT knockdown on cardiac hypertrophy in SHR. For this, small hairpin (sh) RNAs were intravenously injected into SHRs, using a nanoparticle-mediated transfection system. The experimental rats were divided into the following groups: a) Blank control with water treatment only, b) negative control with biscarbamate-crosslinked Gal-polyethylene glycol polyethylenimine nanoparticles (GPE)/negative shRNA, c) AGT-RNA interference (RNAi) group with GPE/AGT-shRNA, and 4) normotensive control using Wistar-Kyoto rats (WKY) with water treatment. Three and five days following the first injection, the levels of hepatic AGT mRNA and AGT protein as well as plasma levels of AGT were markedly decreased in the AGT-RNAi group (P<0.05). Furthermore, a significant decrease in systolic blood pressure (SBP), left ventricular weight to body weight ratio and heart weight to body weight ratio were observed in the AGT-RNAi group compared with those in the control groups. The depletion of AGT in SHR led to a reduction in SBP by 30 +/- 4 mmHg, which was retained for >10 days. Cardiac hypertrophy was also significantly improved in AGT-knockdown rats. In conclusion, the present study showed that AGT-silencing had a significant inhibitory effect on hypertension and hypertensive-induced cardiac hypertrophy in SHRs.