Abstract: BACKGROUND: Recent studies have found that GPE-AGTshRNA nanocomposite cannot only have better transfection efficiency and lower cytotoxicity to hepatocytes in vitro, and also significantly reduce the expression of angiotensinogen at the gene and protein levels.
OBJECTIVE: To observe the effects of angiotensinogen-targeted RNA interference on blood pressure and cardiac protection in spontaneously hypertensive rats, attempting to find a new antihypertensive strategy.
METHODS: Spontaneously hypertensive rats were randomly evenly divided into gene therapy group, negative control group and blank control group, and normal Wistar Kyoto rats (WKY) were set as normal blood pressure control group (WKY group). There were nine sessions in total, with 10 days as one session. On the 1st day of each session, administration in each group was given via the rat tail vein: 500 μL of sterile water for injection in the WKY group, 500 μL of GPE-AGTshRNA nanocomplex in the gene therapy group, and 500 μL of GPE-NC shRNA nanocomplex in the negative control group, and 500 μL of sterile water in the blank control group. We used real-time PCR and western blot assay respectively to detect hepatic angiotensinogen mRNA and protein levels. The serum levels of angiotensinogen and angiotensin II were measured by ELISA. Systolic blood pressure of the tail artery was measured with tail cuff method. Ventricular function was detected by echocardiography. Myocardial lesion was observed under light microscopy.
RESULTS AND CONCLUSION: Angiotensinogen mRNA and protein expression and serum angiotensinogen and angiotensin II levels were significantly lower in the gene therapy group than the negative and blank control groups (P < 0.01). On the 3rd day after the first injection, tail arterial pressure of rats decreased significantly by (28±4) mmHg in the gene therapy group, which was significantly different from that before treatment (P < 0.01). The parameters of left ventricular ejection fraction and left ventricular fractional shortening were significantly increased in the gene therapy group, while the thickness of the left ventricular posterior wall was significantly reduced, and cardiomyocyte hypertrophy were significantly relieved under light microscope. To conclude, angiotensinogen-targeted RNA interference can effectively control blood pressure through downregulation of angiotensinogen, and meanwhile significantly  alleviate myocardial hypertrophy and improve ventricular function.

Key words: hypertension, angiotensinogen, RNA interference, spontaneously hypertensive rats, gene therapy, myocardial hypertrophy