Effects of RNA interference targeting angiotensin 1 receptor and angiotensin-converting enzyme on blood pressure and myocardial remodeling in spontaneous hypertensive rats
10.3760/cma.j.issn.0253-3758.2010.01.017
- VernacularTitle:RNA干扰联合基因沉默ACE和AT1R对自发性高血压大鼠血压及心肌重构的影响
- Author:
Hua ZHOU
1
;
Yun-Fei BIAN
;
Mao-Lian LI
;
Fen GAO
;
Chuan-Shi XIAO
Author Information
1. 山西医科大学第二医院
- Keywords:
Hypertension;
RNA interference;
Ventricular remodeling;
Rats
- From:
Chinese Journal of Cardiology
2010;38(1):60-66
- CountryChina
- Language:Chinese
-
Abstract:
Objective To investigate the effects of RNA interference (RNAi) targeting angiotensin Ⅱ Type 1 receptor (AT1R) and angiotensin-converting enzyme (ACE) on blood pressure and myocardial remodeling in spontaneous hypertensive rats (SHRs). Methods Saline (control), adenovims (Ad5) and recombinant adenoviral vectors (Ad5-ACE-shRNA, Ad5-AT1R-shRNA and Ad5-ACE-AT1R-shRNA expressing ACE, AT1R, ACE and AT1R gene-specific shRNA, respectively) were randomly administered by caudal intravenation to SHBs (n = 12 each group) at day 1 and 17. Normotensive Wistar-Kyoto rats (WKY) served as normal controls. Systolic blood pressure (SBP) of the caudal artery was measured daily. Expression of ACE and AT1R at mBNA levels in ventricle and aorta were evaluated by fluorescence quantitative PCR. Angiotension Ⅱ serum concentration was measured by ELISA at day 3 (n = 6 each group). The ratio of left ventricular to body weight (LVW/BW) and myocardial collagen content were measured, myocardial ultrastructure observed under transmission electron microscope at the study end. Results The caudal artery pressure of saline and Ad5 group was equally increased by about 26 nun Hg(1 mm Hg=0.133 kPa) compared to baseline (both P <0.05). Ad5-ACE-shRNA,Ad5-AT1R-shRNA and Ad5-ACE-AT1R-shRNA injection significantly reduced SBP (-24 mm Hg, -22 mm Hg and -26 mm Hg respectively, all P<0.05 vs. baseline) and the antihypertensive effect could last at least 15 days post each injection. SBP was not affected by saline and Ads injections. ACE and AT1 mRNA expressions at ventricle and aorta were significantly decreased in Ad5-ACE-shRNA, Ad5-ACE-AT1R-shRNA and Ad5-AT1R-shRNA, Ad5-ACE-AT1R-shRNA treated SHRs compared to those in saline and Ad5 groups (all P < 0.05) and was comparable to that in WKY group (P> 0.05). The LVW/BW ratio [(2.22±0.18)μg/mg, (2.23 ±0.19)μg/mg, (2.17±0.16) μg/mg] and myocardial collagen content [(1.291±0.019)μg/mg, (1.298±0.019) μg/mg, (1.276±0.019)μg/mg] in Ad5-ACE-shRNA, Ad5-AT1R-shRNA and Ad5-ACE-AT1R-shRNA treated SHBs were also significantly lower than those in saline treated [(3.23±0.13) μg/mg and(1.683±0.013) μg/mg, both P<0.05] and Ad5 treated SHRs [(3.25±0.12) μg/mg and (1.693±0.013) μg/mg, both P<0.05], but still higher than those of WKY group [(2.06±0.12) μg/mg and (1.258±0.019) μg/mg, both P < 0.05]. Myocardial ultrastructure was also significantly improved in all SHRs underwent RNAi treatments compared to saline and Ad5 treated SHRs. Conclusion RNAi targeting ACE and AT1R gene significantly inhibited myocardial and aortic ACE and AT1R mRNA expressions and resulted in prolonged antihypertensive effects and myocardial ultrastructure improvements in SHRsl. The RNAi technology may be a potential new strategy of gene therapy for hypertension.
