Abstract

Background: Dysregulation of the Renin-Angiotensin-Aldosterone System (RAAS) leads to hypertension and cardiac hypertrophy. Angiotensinogen (AGT) is the only precursor of all angiotensin peptide products. Liver-specific AGT silencing is proven to be a promising treatment option in lowering blood pressure (BP) in patients, but the long-term effects of AGT knockdown on cardiac remodeling is still unclear. Purpose: To explore the long-term effects of R0797070, an AGT targeted RIBO-GALSTARTM(GalNAc)-conjugated siRNA drug, on AGT inhibition, BP and cardiac functions in Spontaneously Hypertensive Rats (SHRs). Methods: In vivo effect of R0797070 was evaluated in SHR. Animals were treated with R0797070 (3 mg/kg, every 8 weeks; subcutaneous injection) or PBS (5 ml/kg, every 8 weeks; subcutaneous injection) for 7 months with the first dose (day1) at the 3 months of age. Captopril (100 mg/kg per day; oral administration) was used as a positive control. Blood pressure was monitored by tail-cuff method after an initial acclimatization training period. Serum AGT protein was measured by ELISA and liver mRNA expression was detected by qPCR. Echocardiography was used to determine the changes of cardiac morphology and functions, and wheat germ agglutinin (WGA) staining was used to measure myocyte cross-sectional size. Results: A single dose of R0797070 at 3 mg/kg resulted in a maximum inhibition of 97% for serum AGT protein with 27 mmHg mean blood pressure (MBP) reduction on Day 15 in SHR. Daily administration of Captopril reduced MBP by 33 mmHg on average, while the duration of drug efficacy of R0797070 could reach 2 months with the average 25 mmHg MBP reduction. At the end of study, the echocardiographic results showed that R0797070 significantly reduced left ve