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Basic science: Cardiovascular disease basic research
e0157 RNA interference targeting ACE and AT1R gene reduced blood pressure and improved myocardial remodelling in SHR
  1. Zhou Hua,
  2. Gao Fen,
  3. Bian Yunfei,
  4. Li Maolian,
  5. Qiu Ling,
  6. Wu Weidong,
  7. He Junhua,
  8. Xiao Chuanshi
  1. The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China

Abstract

Introduction Angiotensin-converting enzyme (ACE) and angiotensin II (Ang II) Type 1 receptor (ATlR) have been shown to play an important role in the pathogenesis of hypertension.

Objective To investigate the effects of RNA interference (RNAi) ATlR and ACE on blood pressure and myocardial hypertrophy in spontaneously hypertensive rats (SHR).

Methods SHRs were treated with normal saline as vehicle controls, with Ad5-EGFP as vector controls, with recombinant adenoviral vectors Ad5-EGFP-ACE-shRNA carrying shRNA for ACE as ACE-RNAi, Ad5-EGFP-AT1R-shRNA carrying shRNA for AT1R as AT1R-RNAi, and Ad5-EGFP-ACE-AT1R-shRNA carrying shRNA for ACE and AT1R as ACE-AT1R-RNAi. WKY rats were taken as normotensive controls treated with normal saline. Systolic blood pressure of the caudal artery was recorded. Serum levels of ACE and Ang II were determined with ELISA. ACE and AT1R mRNA and protein level were determined in myocardium, aorta, kidney and lung. On day-40 of the experiment, heart was pathologically and ultrastructurly examined. The ratio of heart weight to and left ventricular weight to body weight were calculated.

Results Serum concentration of ACE was lower in ACE-RNAi rats, AT1R-RNAi rats and ACE-AT1R-RNAi rats respectively than in vehicle and vector controls (both p<0.05). Serum concentration of Ang II was significantly lower in ACE-RNAi rats and higher in AT1R-RNAi rats than in vehicle and vector controls (p<0.05). The expressions of ACE and AT1R mRNA and protein were significantly reduced in the myocardium, aorta, kidney and lung in ACE-RNAi rats, AT1R-RNAi rats and ACE-AT1R-RNAi rats respectively, compared with that in vehicle and vector controls (all p<0.05). ACE-RNAi, AT1R-RNAi and ACE-AT1R-RNAi treatments resulted in a reduction of systolic blood pressure by (22±6) mm Hg, (20±5) mm Hg, (23±7) mm Hg respectively and the reduction lasted for more than 15 days. In contrast, blood pressure was continuously increased in the vehicle controls as well as vector controls. The ratio of heart weight to and left ventricular weight to body weight were significantly lower in ACE-RNAi rats, AT1R-RNAi rats and ACE-AT1R-RNAi rats respectively than in the vehicle (p<0.05) and vector controls (p<0.05). Myocardial pathology and ultrastructure were also significantly improved in ACE-RNAi rats, AT1R-RNAi rats and ACE-AT1R-RNAi rats, compared with that in vehicle and vector controls.

Conclusions ACE and AT1R silencing had significant antihypertensive effects and reversed hypertensive-induced cardiac hypertrophy in SHR, so RNAi might be a new strategy in control hypertension.

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