Influence Of RAS Inhibitors To Myocardial Hypertrophy Of Two Kidney, One Clip Renovascular Hypertension Rats On ACE2/Angiotensin(1-7)/Mas Receptor

Objective: To study the changes of ACE2/Angiotensin （1-7）/Mas receptor axis,p-ERK1/2and TGF-β₁expression in myocardium of renovascular hypertension ratsand explore the cardioprotective mechanism of two kinds of RAS inhibitors onmyocardial hypertrophy.Methods:98Male Sprague-Dawly rats were randomly divided into shamoperation group （n=18） and2kidney1clip （2K1C） group （n=80）. Hypertensionmodel was established by chronic partial occlusion of left renal artery. Shamoperation group rats underwent the open-abdomen surgery without any renal arteryrestriction. The blood pressure was measured by tail artery sleeve method4weekslater. The successful hypertension model rats （n=66） were randomly divided into2K1C+distilled water group （model group, n=22）,2K1C+Olmesartan group（Olmesartan group, n=22） and2K1C+Zofenopril group （Zofenopril group, n=22）.From the5th week, the model group were gavaged with distilled water at a volumeof10mL/（kg·d）, the Olmesartan group rats were gavaged with Olmesartan at aconcentration of3mg/（kg·d）, the Zofenopril group rats were gavaged with Zofenoprilat a concentration of10mg/（kg·d）. Systolic bood pressures（SBP）, ultrasonography,the body and left ventricle weight were respectively measured at the8th,12th and14th week. The plasma Ang（1-7） and TGF-β₁levels were evaluated by ELISA, themRNA levels of ACE2, Mas and TGF-β₁were detected by RT-PCR, and the ACE2,Mas and p-ERK1/2protein expression were tested by Western blotting.Results:（1）Compared with the sham operation group, the SBP increased significantly in model group rats at the end of the4th,8th,12th and14th week（P<0.01, respectively）. After treated with Olmesartan or Zofenopril, it decreasedmarkedly （P<0.01, respectively）.（2）The end-systolic and diastolic ventricular septalthickness, end-systolic and diastolic left ventricular wall thickness and leftventricular mass index in model group were significantly enhanced compared withsham operation group at the end of the8th,12th and14th week respectively（P<0.01,respectively）. However, after being treated with Olmesartan or Zofenopril, they alldecreased significantly（P<0.01, respectively）.（3） The plasma Ang（1-7） was higherin model group than in sham operation group at the8th and12th week [（20.4±0.57）vs （16.35±0.49）ng/L,（17.18±0.65） vs （16.36±0.45）ng/L, P<0.01, respectively],while no significant difference appeared between them at the14th week （P>0.05）.TGF-β₁level in plasma were significantly higher in model group than in shamoperation group at each point [（22.03±1.09） vs （14.22±1.24）ng/L,（23.95±1.41） vs（14.26±1.28）ng/L,（25.91±1.59） vs （13.98±1.07）ng/L, P<0.01, respectively]. Theplasma Ang（1-7） level in Olmesartan and Zofenopril group increased sharply atthe12th and14th week compared to model group [（20.16±0.52） and （19.26±0.51） vs（17.18±0.65）ng/L,（20.27±0.40） and （19.35±0.39） vs （16.32±0.5）ng/L, P<0.01,respectively] except the8th week[（18.41±0.46） and （18.35±0.46） vs （20.4±0.57）ng/L,P<0.01]. Meanwhile, the plasma TGF-β₁level was reduced significantly at eachpoint in two drug groups [（17.01±1.76） and （16.29±1.41） vs （22.03±1.09）ng/L,（14.66±1.07） and （14.39±1.38） vs （23.95±1.41）ng/L,（14.59±1.10） and （14.48±1.52）vs （25.91±1.59）ng/L, P <0.01, respectively].（4）In contrast to sham operation group,the ACE2and Mas expression in model group were upregulated at the8th week,while downregulated at the12th and14th week. After being treated with Olmesartanor Zofenopril, they both decreased at the8th week while increased at the12th and14th week（P<0.01, respectively）.The mRNA of TGF-β₁and protein expression of p-ERK1/2in model group were higher in each period compared to sham operationgroup（P<0.01, respectively）. After gavaged with Olmesartan or Zofenopril, theywere both reduced significantly （P<0.01, respectively）.Conclusion: Olmesartan and Zofenopril can significantly reduce the bloodpressure and attenuate cardiac hypertrophy of renovascular hypertension rats, whileenhancing the ACE2/Ang （1-7）/Mas receptor axis and reducing the p-ERK1/2andTGF-β₁expression, which may partially contribute to the relevant cardioprotectiveeffect.