Pifithrin-α改善异丙肾上腺素诱导心肌纤维化的作用及机制

The effect and mechanism of Pifithrin-αon isoproterenol-induced cardiac fibrosis

目的探讨Pifithrin-α改善异丙肾上腺素(ISO)诱导心肌纤维化的作用及机制。方法将24只SD雄性大鼠采用信封法随机分为观察组、ISO组和对照组3组,每组8只:观察组和ISO组采用5 mg·kg^(-1)·d^(-1)ISO连续皮下注射1周,观察组再采用2 mg·kg^(-1)·d^(-1)Pifithrin-α腹腔注射1次;对照组连续皮下注射0.9%氯化钠注射液1周。在第4周末时,行超声心动图、血流动力学、心脏重量指数、心肌组织病理学、胶原表达水平和内皮间质转化(EndMT)指标检测。将人微血管内皮细胞分为观察组、转化生长因子-β(TGF-β)组和对照组3组,前两组细胞采用TGF-β刺激,对照组细胞正常培养78 h,检测3组细胞EndMT指标。结果观察组大鼠左心室舒张末期内径、左心室舒张末期压、左心室重量指数及右心室重量指数低于ISO组,左心室后壁厚度、左心室平均收缩压、左心室压力最大上升速率及左心室压力最大下降速率高于ISO组,差异均有统计学意义(均P<0.05)。观察组大鼠胶原体积分数、Ⅰ型胶原和Ⅲ型胶原表达水平低于ISO组,差异均有统计学意义(均P<0.05)。观察组大鼠心肌组织α-平滑肌肌动蛋白(α-SMA)、波形蛋白和p53表达水平低于ISO组,分化簇31(CD31)表达水平高于ISO组,差异均有统计学意义(均P<0.05)。观察组细胞α-SMA、波形蛋白和p53表达水平低于TGF-β组,CD31表达水平高于TGF-β组,差异均有统计学意义(均P<0.05)。结论Pifithrin-α可有效减轻ISO诱导的大鼠心肌纤维化和改善心功能,其机制可能与抑制p53介导的EndMT有关。

Objective To investigate the role and mechanism of Pifithrin-αon isoproterenol(ISO)-induced cardiac fibrosis in rats.Methods Twenty-four SD male rats were randomly divided into observation group,ISO group and control group.The observation group and ISO group received subcutaneous injection of ISO 5 mg·kg^(-1)·d^(-1)for 1 week,and then the observation group was injected intraperitoneally 2 mg·kg^(-1)·d^(-1)Pifithrin-αonce.The control group received subcutaneous injection of 0.9%sodium chloride solution for 1 week.At the end of 4 weeks,echocardiography,hemodynamic analysis,cardiac weight index,histopathology of myocardial tissues,collagen expression and endothelial-to-mesenchymal transition(EndMT)markers were detected.Human microvascular endothelial cells(HMVECs)were divided into 3 groups:observation group,transforming growth factor-β(TGF-β)group and control group;the first two groups were stimulated with TGF-β,control group cells were culture for 78 h and EndMT markers were detected in all cells of 3 groups.Results In the observation group,LVEDd,LVEDP,LVWI and RVWI were lower than the ISO group,and LVPWd,LVSP,+dp/dtmax and-dp/dtmax were higher than the ISO group,all with a significant difference(all P<0.05).The collagen volume fraction,collagenⅠand collagenⅢexpression in the observation group,were lower than the ISO group,all with a significant difference(all P<0.05).In the observation group of rat myocardial tissues,the expression ofα-SMA,vimentin and p53 was lower than the ISO group,and the CD31 expression was higher than the ISO group,all with a significant difference(all P<0.05).In the observation group of cells,the expression ofα-SMA,vimentin,and p53 cells was lower than the TGF-βgroup,and CD31 expression was higher than the TGF-βgroup,all with a significant difference(all P<0.05).Conclusion Pifithrin-αcan effectively prevent ISO induced myocardial fibrosis and improve cardiac function in rats,and the mechanism may be related to the inhibition of p53-mediated EndMT.