Ghrelin对心衰心肌纤维化的影响及机制研究

Study on the mechanism of ghrelin down-regulating Act A/ActRIIA expression to inhibit myocardial fibrosis in heart failure

目的阐明Ghrelin对心梗后心衰心肌纤维化的影响及其可能机制。方法采用结扎左冠状动脉前降支的方法构建心梗后心衰大鼠模型,并在术后将动物随机分为心衰模型组(给予生理盐水)和Ghrelin治疗组,并设立假手术对照组。术后第5周开始皮下注射Ghrelin,连续给药4周。通过心脏超声检查评价各组大鼠心功能;HE染色观察心肌重构;Masson染色观察心肌纤维化,并应用PCR法检测Ⅰ型及Ⅲ型胶原以及激活素(Activin,Act)A表达;免疫组织化学染色法检测Act A及其受体(ActRIIA)表达水平。结果与假手术组相比,模型组大鼠的左室射血分数(EF)明显下降;Ⅰ型及Ⅲ型胶原mRNA表达明显增加,心肌纤维化程度明显加重,心肌重构显著;Act A及ActRIIA表达水平明显增高。与模型组相比,Ghrelin治疗组EF显著提高;Ⅰ型及Ⅲ型胶原mRNA表达明显减少,心肌纤维化程度明显减轻;Act A及ActRIIA表达水平水平明显下降。结论 Ghrelin可抑制心肌纤维化改善心肌重构,进而提高心衰大鼠心功能,其机制可能与Ghrelin下调Act A及其受体ActRIIA表达,减少并阻断Act A的作用途径有关。

Objective To elucidate the effect of ghrelin on myocardial fibrosis after myocardial infarction(MI)and its possible mechanism.Methods Rat model of heart failure after MI was established by ligation of the left anterior descending(LAD).After surgery,the animals were randomly divided into the model group(MI-normal saline)and the ghrelin treatment(MI-Ghrelin)group,and the sham operation(SO)control group was compared.Subcutaneous injection of ghrelin was started at the 5 th week after surgery and continued for 4 weeks.Cardiac function of each group was assessed by cardiac ultrasonography.Masson staining was used to observe myocardial fibrosis.Masson staining was used to observe myocardial fibrosis,and PCR was used to detect the expression of type I andⅢcollagen and Act A.In addition,the expression levels of Act A and ActRIIA were detected by immunohistochemical staining.Results Compared with the sham operation group,the left ventricular ejection fraction(EF)of the model group was significantly decreased.The expression of type I and typeⅢcollagen was significantly increased,myocardial fibrosis was significantly aggravated,and myocardial remodeling was significant.The expression levels of Act A and ActRIIA were significantly increased.Compared with the model group,EF was significantly increased in the ghrelin treatment group;The expression of type I and typeⅢ collagen was significantly reduced,and myocardial fibrosis was significantly alleviated.The expression levels of Act A and ActRIIA were significantly decreased.Conclusion By down-regulating the expression of Act A and ActRIIA,ghrelin may reduce the expression of Act A or block its action pathway,thereby inhibiting myocardial fibrosis and improving myocardial remodeling,thus improving cardiac function in rats with heart failure.