内源活性肽Apelin-13对高血压大鼠心肌纤维化的影响及机制

Effect of apelin-13 on myocardial fibrosis in hypertensive rats and its underlying mechanism

目的探讨内源性活性肽Apelin-13对高血压大鼠心肌纤维化(myocardial fibrosis,MF)的影响并初步探讨其机制。方法将40只8周龄雄性SD大鼠随机分组,对其中32只大鼠施行腹主动脉狭窄(abdominal aorta coarctation,AAC)术,8只施行假手术,将造模后成活的大鼠随机分成模型组、Apelin-13组(10μg/kg),缬沙坦(valsartan,VST)组[5 mg/(kg·d)]。观察Apelin-13对高血压大鼠心脏功能及血流动力学指标的影响;ELISA法测定血清Ang(1-7)、AngⅡ的浓度;Western观察大鼠心肌转化生长因子β1(transforming growth factor beat 1,TGF-β1)、组织抑制因子(tissue inhibitor of metalloproteinase,TIMP)、血浆纤溶酶原激活抑制剂-1(plasminogen activator onhibitor,PAI-1)、金属蛋白酶-2(matrix metalloproteinase 2,MMP-2)的表达水平;HE和Masson染色观察心肌组织胶原沉积情况,图像分析测量心肌组织胶原容积分数(collagen volume fraction,CVF)。结果心功能AAC组较假手术组、Apelin-13组、VST组明显降低(P<0.05),VST组较Apelin组减低(P<0.05)。血清Ang-(1-7)AAC组较药物治疗组降低,Ang(Ⅱ)增加(P<0.05),Apelin组与VST组差异无统计学意义(P>0.05)。Apelin-13组、VST组和AAC组中CVF及蛋白TIPM-1、TGF-β1、PAI-1的表达高于假手术组(P<0.05),且两种药物治疗组明显低于AAC组,Apelin-13组低于VST组(P<0.05),而MMP-2蛋白的表达低于假手术组。结论 Apelin-13可能通过抑制肾素-血管紧张素-醛固酮系统,进而抑制TGF-β1、PAI-1、TIMP-1和增加MMP-2的表达以改善高血压心肌纤维化。

Objective To study the effect of apelin-13 on myocardialfibrosis in hypertensive rats and its underlying mechanism. Methods Forty male Sprague Dawley （SD） rats aged 8 weeks were randomly divided into AAC group （n=32） and sham operation group （n=8）. After modeling the survival, the rats were randomly divided into three groups： apelin-13 group （n=8）, valsartan VST group （n=8） and model group （n=8）. The effect of apelin-13 on their cardiac function status and hemodynamical indexes were tested. ELISA kit was used to measure the concentration of AngⅡand Ang （1-7） in blood; Expression level of signaling pathways related protein TGF-β1, TIMP, PAI-1 and MMP-2 were detected by Western-blotting; Morphology of collagen in myocardial tissue was observed by HE and Masson staining, collagen volume fraction （CVF） in left ventricular interstitial tissue was measured by image analysis.Results The cardiac function of AAC group decreased significantly compared with the sham operation group, apelin-13 group and VST group （P〈0.05）, and VST group waslower than apelin-13 group. Compared with the drug treatment group, the serum levels of Ang-（1-7） in ACC group decreased while the serum levels of Ang （Ⅱ） increased （P〈0.05）, and no statistically significant difference was found between apelin-13 group and VST group （P〉0.05）. The CVF in left ventricular interstitial tissue, and the TGF-β1, TIMP, PAI-1 protein expression levels were significantly higher whereas the MMP-2 expression level was significantly lower in apelin-13 group, VST group and ACC group than in sham operation group （P〈0.05）, and both drug treatment groups were significantly lower than AAC group with apelin-13 group lower than VST group （P〈0.05）.Conclusion Apelin-13 can improve myocardialfibrosis in hypertensive rats by inhibiting the renin - angiotensin - aldosterone system, thereby inhibiting the expression of TGF-β1, PAI-1, TIMP-1 and improving the expression of MMP-2.