Effect and mechanism of angiotensin(1-7)supplementation combined with exercise therapy on cardiac remodeling in rats with renal hypertension / 中国组织工程研究

ABSTRACT

BACKGROUND:The renin-angiotensin system plays a key role in the occurrence and development of hypertension,in which angiotensin(1-7)has antihypertensive effect and reversely regulates the adverse effects of angiotensin Ⅱ.Exercise rehabilitation therapy is an important non-pharmaceutical means to prevent and treat hypertension;however,whether angiotensin(1-7)and exercise have a synergistic effect is not yet clear. OBJECTIVE:To explore the effect of angiotensin(1-7)supplementation combined with exercise therapy on cardiac remodeling in rats with renal hypertension and to investigate the possible mechanism of angiotensin(1-7)and its receptor signal axis. METHODS:Sixty male Sprague-Dawley rats were selected,of which 12 rats were randomly selected as normotensive group and the remaining 48 rats were used to make animal models of renal hypertension using two-kidney one-clip method and were then randomly divided into hypertension control group,hypertension exercise group,angiotensin(1-7)group and combined treatment group.One week after successful modeling,different interventions were given(for a period of 6 weeks)as follows:the hypertension exercise group was subjected to a running training on an electric treadmill,the angiotensin(1-7)group was perfused with angiotensin(1-7)by implanting Alzet microosmotic pump subcutaneously on the back of the rats,and the combined treatment group was perfused with angiotensin(1-7)after running training,while the normotensive group and hypertension control group were caged quietly.At 48 hours after the last training session,the tail artery blood pressure was measured with a non-invasive sphygmomanometer;the heart structure and function were detected by echocardiography;the left ventricular myocardium was taken for histopathological observation by hematoxylin-eosin and Masson staining,and the cardiomyocyte cross-sectional area and collagen volume fraction were obtained by image analysis software as markers of myocardial hypertrophy and fibrosis,respectively;the content of angiotensin(1-7)in the heart was detected by high performance liquid chromatography;the mRNA expression of cardiac embryonic genes,atrial natriuretic peptide and β-myosin heavy chain,was detected by real-time fluorescence quantitative PCR;and the protein expression of cardiac Mas receptor,angiotensin Ⅱ type 2 receptor and endothelial nitric oxide synthase was measured by western blot assay. RESULTS AND CONCLUSION:Compared with the normotensive group,blood pressure increased(P<0.05),cardiac function had no significant changes(P>0.05),cardiomyocyte cross-sectional area and collagen volume fraction increased(P<0.05),mRNA expression of atrial natriuretic peptide and β-myosin heavy chain was upregulated(P<0.05),angiotensin(1-7)content and protein expression of Mas receptor,angiotensin Ⅱ type 2 receptor and endothelial nitric oxide synthase was downregulated(P<0.05)in the hypertension control group.Compared with the hypertension control group,blood pressure decreased(P<0.05),cardiac function improved(P<0.05),collagen volume fraction decreased(P<0.05),cardiomyocyte cross-sectional area and angiotensin(1-7)content showed no significant changes(P>0.05),mRNA expression of atrial natriuretic peptide and β-myosin heavy chain was downregulated(P<0.05),and the protein expression of Mas receptor,angiotensin Ⅱ type 2 receptor and endothelial nitric oxide synthase was upregulated(P<0.05)in the hypertension exercise group;except for an increase in myocardial angiotensin(1-7)content(P<0.05),other parameters had no statistical significance(P>0.05)in the hypertension angiotensin(1-7)group.Compared with the hypertension exercise group,blood pressure decreased(P<0.05),cardiomyocyte cross-sectional area and cardiac function had no significant changes(P>0.05),collagen volume fraction decreased(P<0.05),angiotensin(1-7)content increased(P<0.05),mRNA expression of atrial natriuretic peptide and β-myosin heavy chain was downregulated(P<0.05),and the protein expression of Mas receptor,angiotensin Ⅱ type 2 receptor and endothelial nitric oxide synthase was upregulated(P<0.05)in the combined treatment group.To conclude,supplementation of angiotensin(1-7)alone cannot improve cardiac remodeling in rats with renal hypertension,but it can enhance the efficacy of exercise.The mechanism is related to the improvement of angiotensin(1-7)receptor deficiency and restoration of its signaling pathway function.