淫羊藿苷抗心肌纤维化作用及机制研究

Myocardial fibrosis (MF) is a key factor of cardiac dysfunction from compensatory stage to decompensatory one. The major cause for MF is the excessive proliferation of myocardial fibroblasts (CFs) and the accumulation of collagen. MF is an amazingly complicated process, and the ideal therapeutic drugs for this disease are still unavailable to date. Thus, it is very important to quest for new therapeutic drugs for MF. Epimedium, abundant in Guizhou Province, is the traditional Chinese medicine, which posses the efficacy of warmly invigorating kidney yang, reinforcing cardiac efficiency. Icariin (ICA) is one of its main active ingredient, with less toxic. Series of studies reported that it may play important role in regulating those significant factors which affect the fibroblasts proliferation and collagen deposition. It is presumed that ICA should have anti-MF, and our preliminary study found that ICA had the anti-MF effect in spontaneously hypertensive rats (SPR). Therefore, the current study is designed to systematically observe the effect of Icariin on myocardial fibrotic formation and to acquire the conclusive evidence for identifying its anti-MF effect in SHR. Furthermore, to explore the mechanism is whether or not to affect the expression of transforming growth factor 1 (TGF-β1) and SMAD2，and so on. The objective of the present study is to provide basic pharmacological data for ICA, the main active ingredient of Epimedium, to be used in the treatment of MF.

心肌纤维化（MF）是心功能不全代偿期向失代偿期转变的关键，目前缺乏针对性治疗药物，故探索抗MF的新药具有重要意义。淫羊藿为我省道地中药材，有“补肾阳，强心力”等功效，淫羊藿苷(ICA)是其主要活性成分之一，毒性低，系列研究报道ICA在其他疾病中可影响调控与MF共同的分子基础，故推测ICA可能通过影响CFs过度增殖及胶原沉积的调控因素而具有抗MF效应。本课题组的预实验研究提示ICA可能具有抗MF作用。因此本项目首先通过自发性高血压大鼠MF模型，研究ICA的抗MF效应，并观察ICA对SHR的左心室转化生长因子β（TGF-β）-SMAD2信号等影响；分析其作用机制。本项目旨在为中药淫羊藿的主要活性成分ICA用于MF的治疗提供基础药理学依据，研究高效低毒的抗MF药物。。

心肌纤维化（MF）是心功能不全代偿期向失代偿期转变的关键，目前缺乏针对性治疗药物，故探索抗MF的新药具有重要意义。淫羊藿为我省道地中药材，有“补肾阳，强心力”等功效，淫羊藿苷(ICA)是其主要活性成分之一，毒性低，系列研究报道ICA在其他疾病中可影响调控与MF共同的分子基础，故推测ICA可能通过影响CFs过度增殖及胶原沉积的调控因素而具有抗MF效应。本项目首先通过自发性高血压大鼠MF模型，研究ICA的抗MF效应，并应用分子生物学技术观察ICA对SHR的左心室转化生长因子β（TGF-β）- SMAD2信号、MMP-9 、TIMP-1 等影响，分析其作用机制。14周龄雄性SHR大鼠随机分为模型组、Ica低剂量组（20mg/kg）、中剂量组（40mg/kg）、高剂量组（80mg/kg），联合氯沙坦组（ICA80mg/kg+氯沙坦20 mg/kg），阳性组（氯沙坦20 mg/kg），灌胃给药每日二次至26周龄，14周龄雄性WKY大鼠为空白对照组，空白和模型组给予等体积的双蒸水，实验结束后处死全部动物。本实验研究发现，与空白对照组相比，模型组左心室功能降低，血压明显升高，左心指数增加，僵硬度增加，羟脯氨酸、Ⅰ型和Ⅲ型胶原含量显著增加，TGF-β1、SMAD2、MMP-9 、TIMP-1 mRNA含量增加；TGF-β1、SMAD2蛋白表达上调；与模型组相比，淫羊藿苷低、中、高组和联合使用氯沙坦组的左心室功能增加，血压下降，左心指数减小，羟脯氨酸、Ⅰ、Ⅲ型胶原含量降低，TGF-β1、SMAD2、MMP-9 mRNA表达降低，TIMP-1mRNA表达增加，TGF-β1、SMAD2蛋白表达下调。可以认为，淫羊藿苷具有抗自发性高血压大鼠心肌纤维化的作用，其机制与TGF-β1- SMAD2通路有关。