摘要
心肌梗死(myocardial infarction, MI)是因冠状动脉或其分支阻塞而引起的缺血性心肌病,可导致心室重构,并可逐步进展为心力衰竭(heart failure, HF),严重威胁人类的健康和生命。心肌纤维化(myocardial fibrosis, MF)是多种心脏疾病发展到一定阶段的共同病理改变,是最具特征性的结构改变之一,为MI后心室重构的主要表现之一,可促进心肌收缩和舒张功能失调。心肌成纤维细胞(cardiac fibroblasts,CFs)的长期激活,即增强的细胞增殖、肌成纤维细胞分化和伴随的细胞外基质(extracellular matrix, ECM)分泌,可导致心肌纤维化。
转化生长因子-p1(transforming growth factor-β1, TGF-β1)是最重要的促纤维化生长因子,为诸多因素所致MF的共同通路。MI后TGF-β1的表达显著性升高；而体内基因转染TGF-β1可诱导MF。为深入了解TGF-β1信号通路抑制对MI后MF过程的调控机制,本研究首先从细胞水平探讨了该信号通路抑制与CFs的生物学效应之间的关系。
培养新生大鼠的CFs,随机分为四组：PBS组、TGF-β1组、可溶性转化生长因子一β1Ⅱ型受体(soluble transforming growth factor-β1 receptorⅡ, sTβRⅡ)组和TGF-β1+sTβRⅡ组。MTT法检测CFs的增殖。α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)免疫细胞化学染色检测肌成纤维细胞分化。免疫细胞化学染色和Western blot分析检测TGF-β1信号通路中关键的信号分子P-Smad2和Smad2/Smad3蛋白的表达水平。结果表明,与PBS组相比较,TGF-β1组CFs的增殖、肌成纤维细胞分化和P-Smad2蛋白的表达均显著性升高(P<0.01)；与TGF-β1组相比较,TGF-β1+sTβRⅡ组CFs的增殖、肌成纤维细胞分化和P-Smad2蛋白的表达均显著性降低(P<0.01)；各组间Smad2/Smad3总蛋白的表达水平无显著性差异(P>0.05)。以上结果提示,TGF-β1可激活Smad信号,诱导CFs的增殖和肌成纤维细胞分化；sTβRⅡ预处理可抑制TGF-β1诱导的Smad信号的激活和下游事件,即CFs增殖和肌成纤维细胞分化,从而抑制CFs的功能。
此外,Wnt信号通路是脊椎动物发育过程中起关键作用的信号通路之一,参与了胚胎心脏的发育过程。而心脏病理过程中胚胎基因的重新表达是一种被普遍观察到的现象。研究表明,Wnt信号通路参与了MI后的组织修复过程。为深入了解Wnt信号通路抑制对MI后MF过程的调控机制,本研究进而探讨了该信号通路抑制与CFs的生物学效应之间的关系。
培养新生大鼠的CFs,随机分为四组：PBS组、Wnt-1组、分泌型卷曲相关蛋白-1(secreted frizzled related protein-1, sFRP-1)组和Wnt-1+sFRP-1组。MTT法检测CFs的增殖。α-SMA免疫细胞化学染色检测肌成纤维细胞分化。免疫细胞化学染色和Western blot分析检测Wnt信号通路中的两个关键性信号分子dishevelled-1(DVL-1)和β-连环蛋白(p-catenin)的表达水平。结果表明,与PBS组相比较,Wnt-1组CFs的增殖、肌成纤维细胞分化、DVL-1和β-catenin的表达均显著性升高(P<0.01)；与Wnt-1组相比较,Wnt-1+sFRP-1组CFs的增殖明显降低(P<0.05)、肌成纤维细胞分化、DVL-1和β-catenin的表达均显著性降低(P<0.01)。以上结果提示,Wnt-1可激活Wnt信号通路,诱导CFs增殖和肌成纤维细胞分化；而sFRP-1预处理可拮抗Wnt-1的作用,抑制Wnt信号通路的激活和下游事件,即CFs增殖和肌成纤维细胞分化,抑制CFs的生物学功能。
为了进一步阐明TGF-β1信号通路和Wnt信号通路阻断对MI后MF过程的调控机制,我们通过结扎大鼠左冠状动脉前降支制作MI模型,4天后存活的大鼠随机进行处理并分组：假手术组(给予等量PBS,n=10)、MI组(给予等量PBS,n=10)、MI+sTβRⅡ组(在梗死区和梗死边缘区注射100ng sTβRⅡ/20μl PBS, n=10)、MI+sFRP-1组(在梗死区和梗死边缘区注射100ng sFRP-4/20μl PBS, n=10)和MI+sTβRⅡ+sFRP-1组(给予100ng sTβRⅡ/10μl PBS和100ng sFRP-1/10μl PBS,n=10)。2周后,4只/组大鼠被处死,冰冻切片,a-SMA免疫组化染色检测肌成纤维细胞分化；4周后,测量血流动力学指标评价心功能,并计算重量参数和梗死面积。结果表明,与MI组相比较,MI+sTβRⅡ、MI+sFRP-1和MI+sTβRⅡ+sFRP-1组肌成纤维细胞分化显著性减少(P<0.01),左心室收缩压明显升高、左心室末期舒张压明显降低、左心室最大变化速率明显升高(P<0.01),心脏重/体重、左心室重/体重明显减轻(P<0.05),梗死面积显著性减少(P<0.05)。而MI+sTβRⅡ+sFRP-1组的变化最为显著。以上结果提示,联合应用sTβRⅡ和sFRP-1同时阻断TGF-β1信号通路和Wnt信号通路,可抑制肌成纤维细胞分化,有效缓解MF和左心室重构,改善缺血性心肌功能。
综上所述,本研究从体内和体外两方面证实了TGF-β1和Wnt信号通路阻断对心梗后MF过程的调控,为将来可能进行的临床干预提供了新的思路。
Myocardial infarction (MI), an ischemic cardiomyopathy caused by occlusion of coronary arteries or its branches, often leads to left ventricular remodeling, advances on heart failure (HF) gradually, and is a threat against human health and lives. Myocardial fibrosis (MF), one of the most characteristic structural changes, is the common pathologic change of multiple heart diseases and one of the principal manifestations of left ventricular remodeling, and contributes to both systolic and diastolic dysfunction. Prolonged activation of cardiac fibroblasts (CFs), defined by increased cell proliferation, myofibroblast differentiation and subsequent extracellular matrix (ECM) secretion, leads to myocardial fibrosis.
Transforming growth factor-β1 (TGF-β1), the major contributor to tissue fibrosis, is the mutual pathway of myocardial fibrosis caused by a variety of factors. The expression of TGF-β1 is markedly increased in both infarcted and non-infarcted areas of the hearts after MI. In vivo gene transfer of TGF-β1 can induce myocardial fibrosis. To clarify the regulatory mechanism of TGF-β1 signaling inhibition on myocardial fibrosis after MI, we first designed in vitro experiments.
CFs were cultured and treated respectively with PBS, TGF-β1, soluble transforming growth factor-β1 receptorⅡ(sTβRⅡ), and TGF-β1+sTβRⅡ. CFs proliferation was measured by MTT assay. Myofibroblast differentiation was examined by a-smooth muscle actin (a-SMA) immunocytochemical staining. The expression of P-Smad2 and Smad2/Smad3, the critical signaling molecules, were determined by immunocyto-chemical staining and Western blot analysis. Results demonstrated that TGF-β1 significantly increased CFs proliferation, myofibroblast differentiation and the expression of P-Smad2 compared with PBS group (P<0.01); CFs proliferation, myofibroblast differentiation and the expression of P-Smad2 in TGF-β1+sTβRⅡgroup were reduced markedly compared with TGF-β1 group (P<0.01). There were no significant differences in the expression of total Smad2/Smad3 among the 4 groups (P>0.05). These results showed that TGF-β1 induced the activation of Smad signaling, CFs proliferation and myofibroblast differentiation; while pretreatment with sTβRⅡinhibited TGF-β1-induced the activation of Smad signaling and its downstream events, I.e. cell proliferation and myofibroblast differentiation, and consequently inhibited CFs function.
In addition, Wnt signal pathway is thought to be functionally conserved in vertebrates and plays an important role in organogenesis, and is found to participate in the development of fetal heart. In cardiovascular pathology, re-expression of a fetal gene expression pattern is a generally observed phenomenon. Several studies suggested that Wnt signal pathway might be involved in the repair process after MI. To illustrate the regulatory mechanism of Wnt signaling inhibition on myocardial fibrosis after MI, we designed the following experiments in vitro.
CFs were cultured and treated respectively with PBS, Wnt-1, secreted frizzled related protein-1 (sFRP-1), and Wnt-1+sFRP-1. Cell proliferation was measured by MTT assay. Myofibroblast differentiation was examined byα-SMA immunocytochemical staining. The expression of dishevelled-1 (DVL-1) andβ-catenin, two critical signaling molecules, were determined by immunocytochemical staining and Western blot analysis. Results demonstrated that Wnt-1 significantly increased CFs proliferation, myofibroblast differentiation, and the expression of DVL-1 andβ-catenin compared with PBS group (P <0.01); CFs proliferation (P<0.05), myofibroblast differentiation, and the expression of DVL-1 andβ-catenin in Wnt-l+sFRP-1 group were reduced markedly compared with Wnt-1 group (P<0.01). These results indicated that Wnt-1 induced the activation of Wnt signal pathway, CFs proliferation and myofibroblast differentiation; whereas pretreatment with sFRP-1 antagonized the action of Wnt-1, inhibited the activation of Wnt signal pathway and its downstream events, that is CFs proliferation and myofibroblast differentiation, and thus inhibited CFs function.
To clarify the mechanism that blockade of TGF-β1 signal pathway and Wnt signal pathway may control the process of myocardial fibrosis after MI, we prepared MI model by ligation of the left anterior descending coronary artery.4 days after the coronary ligation, MI rats that had survived were treated and divided into groups at random: Sham-operated group (equal PBS, n=10), MI group (equal PBS, n=10), MI+sTβRⅡgroup (100ng sTβRⅡ/20μl PBS was injected into the infarct myocardium border and the infarct area, n=10), MI+sFRP-1 group (100ng sFRP-1/20μl PBS was injected into the infarct myocardium border and the infarct area, n=10), and MI+sTβRⅡ+sFRP-1 group (100ng sTβRⅡ/10μl PBS and 100ng sFRP-1/10μl PBS, n=10).2 weeks after treatment, 4 rats per group were killed and made frozen section, and myofibroblast differentiation was measured with a-SMA immunohistochemical staining.4 weeks after treatment, cardiac function was evaluated by hemodynamic measurement, weight parameters and infarct size were detected with a previous experimental method. Results demonstrated that compared with MI group, MI+sTβRⅡ, MI+sFRP-1, and MI+sTβRⅡ+sFRP-1 significantly reduced myofibroblast differentiation (P<0.01), improved left ventricular systolic pressure and the maximum rate of left ventricular systolic pressure rise and fall, but decreased left ventricular end-diastolic pressure (P<0.01), markedly reduced the ratio of heart weight and body weight, and the ratio of left ventricular weight and body weight (P<0.05), and significantly reduced infarct size (P<0.05). However, these changes are more significant in MI+sT(3RⅡ+sFRP-1 group. These results suggested that combination of sTβRⅡand sFRP-1 blocked TGF-β1 and Wnt signal pathway could inhibit myofibroblast differentiation, alleviate myocardial fibrosis and left ventricular remodeling, and improve ischemic cardiac function effectively.
For all the above, the present study verified the manipulation of blockade of TGF-β1 and Wnt signal pathway to the process of myocardial fibrosis after MI both in vivo and in vitro, and thus represented a new approach for future therapeutic interventions.
引文
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