| objective: In order to explore new mechanisms of cardiac hypertrophy and associated molecular mechanism of irbesartan which can improve myocardial hypertrophy, to provide preliminary experimental basis for clinic to prevent and treat left ventricular remodeling which caused by high blood pressure in mi RNA levels. Methods: Twenty four ten-week-old male SPF(specific pathogen free) SHRs were randomly divided into four groups, six in each group: placebo group(SHR group), Irb50 group(irbesartan 50 mg / kg / d), Irb100 group(irbesartan 100 mg / kg / d), Irb200 group(irbesartan 200 mg / kg / d). Meanwhile six 10-week-old male SPF Wistar-Kyoto(WKY) rats as control group. Drug intervention groups were administered once a day for 16 weeks, while the SHR and WKY groups were fed with the same amount of distilled water as a control. All rats were fed for 16 weeks. The effect of irbesartan was determined by changes in blood pressure, left ventricular mass index(LVMI), myocardial histopathological staining, transverse diameter of myocardium(TDM) and collagen volume fraction(CVF). Total RNA was extracted from the left ventricular tissue at the same time, and the difference of mi RNA expression profiles in myocardial tissue after drug intervention was detected by using mi RNA microarray.Results: Our study show: 1. Systolic and diastolic blood pressure of rats in irbesartan intervention groups decreased significantly with dose increasing compared with the SHR group(P<0.01). 2. HE staining showed that left ventricular myocardial cells in SHR rats were hypertrophic, and myocardial interstitial and collagen fibers increased to some extent, LVMI, TDM and CVF in SHRs decreased after intervention of different doses irbesartan(P<0.05) compared with the placebo group. LVMI, TDM and CVF in Irb200 intervention group was significantly lower than Irb50 and Irb100 intervention group.3.Compared with control group, there were 228 differentially expressed mi RNA in mi RNA expression profile of left ventricular myocardium of SHR group, of which 159 mi RNA expression was significantly up-regulated, 69 mi RNA remarkably down-regulated. After different doses of irbesartan, there were 53 mi RNA significantly up-regulated, 18 mi RNA significantly down-regulated compared Irb50 intervention group with SHR group; there were 20 mi RNA significantly up-regulated, 19 mi RNA significantly down-regulated when compared the intervention group with the SHR group Irb100; there were 19 mi RNA significantly increased, 56 mi RNA significantly reduced when compared the intervention group with the SHR group Irb200. 4. Four mi RNAs were ten times up-regulated in SHR group, contrast to the control group, namely: mi R-122-5p, mi R-184, mi R-30c-1-3p and mi R-504,farther more mi R-122-5p up to 200 times. And there were four mi RNAs which were ten times down-regulated in SHR group, contrast to the control group, namely: mi R-92b-5p, mi R-702-5p, mi R-3557-3p and mi R-466b-5p. Four mi RNAs were ten times up-regulated in Irb50 group, contrast to the SHR group, namely: mi R-204-5p, mi R-204-3p, mi R-487b-3p and mi R-382-5p. There was no 10 times downregulated mi RNA. Two mi RNAs were ten times up-regulated in Irb200 group, contrast to the SHR group, namely: mi R-138-1-3p and mi R-382-5p. And there were 8 mi RNAs which were ten times down-regulated in Irb200 group than in the control group, respectively: mi R-547-5p, mi R-872-3p, mi R-344 g, mi R-29b-3p, mi R-187-3p, mi R-1843-3p, mi R-326- 3p and mi R-122-5p. In which mi R-122-5p were dow-nregulated most obviously, suggesting that mi R-122-5p is likely to be the key mi RNA when irbesartan improves hypertensive left ventricular remodeling.Conclusion: This study shows that irbesartan improve myocardial hypertrophy and myocardial fibrosis in dose-dependent miner. The mi RNA expression profiles change significantly in SHRs with left ventricular hypertrophy tissue indicates that mi RNA is involved in cardiac remodeling. Mi R-122-5p may be the key mi RNA of ventricular remodeling. The results suggest that irbesartan is likely to reverse cardiac remodeling by regulating the expression levels of mi RNA, which helps clinical to diagnose and treat left ventricular hypertrophy in mi RNA level. |
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