曲尼司特对大鼠心肌梗塞后心肌纤维化及TGF-β1表达的影响
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摘要
心肌梗塞后(myocardial infarction,MI)发生的左心室重构(left ventricularremodeling,LVR)是指MI后由于心脏负荷及各种神经体液等因素改变导致的左心室大小、形态、组织结构及功能状态的改变,并贯穿于整个病程的始终,成为影响MI近远期预后的主要原因之一,是从心梗发展为心衰(heart failure,HF)的重要病理生理过程。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MI后心肌重构的主要表现之一,以往的研究主要是从大体形态上观察,现在已深入到细胞分子水平,其中转化生长因子-β_1(transforming growth factor-β_1,TGF-β_1)是这一过程的重要生物活性因子。体内和体外实验都表明,TGF-β_1的过度表达与心脏肥大和MF密切相关,TGF-β_1上调Ⅰ、Ⅲ型胶原合成并抑制胶原酶的释放,促进MF的发生。曲尼司特(tranilast)作为一种抗变态反应药物,可以通过稳定肥大细胞和嗜碱性粒细胞的细胞膜,抑制过敏性物质释放,治疗过敏性鼻炎、过敏性哮喘和过敏性皮炎。近年来发现它能够下调TGF-β_1表达,并抑制瘢痕疙瘩和高度增生性瘢痕中的胶原形成。据文献报道,曲尼司特可抑制TGR(mRen2)高血压和两肾一央高血压大鼠MF。
目的:基于曲尼司特抑制TGF-β_1和抗纤维化的作用,本实验应用抗纤维化药物曲尼司特治疗MI大鼠,观察曲尼司特对大鼠MI后左心室MF和TGF-β_1表达的影响。材料与方法:大鼠35只,结扎大鼠左冠状动脉前降支,造成实验性心肌梗塞,将术后48h存活的大鼠随机分成三组:曲尼司特治疗组(n=13)、MI模型组(n=12)和假手术组(n=10)。假手术组大鼠,仅做开胸,在冠状动脉相同部位穿线,不结扎;曲尼司特治疗组大鼠:灌胃给药,剂量为400 mg·kg~(-1)·d~(-1)分两次给予;其他大鼠给予等量生理盐水。术后4周,颈动脉插管八导记录仪测量血流动力学指标评价心功能。计算左心室重量与体重之比以评价心室肥大情况。HE染色观察心肌组织形态学变化并计算梗死面积。免疫组化方法检测TGF-β_1的表达,氯胺T法测定左室非梗死区羟脯氨酸(HYP)含量。实验结果:与假手术组比较,MI对照组左室舒木压(LVEDP),左心室重量与体重之比,TGF-β_1的表达,羟脯氨酸含量均显著升高(P均＜0.01),而左室收缩压(LVSP),左室压力上升和下降最大变化速率(±dP/dt)显著下降(P＜0.01)。与MI模型组比较,曲尼司特治疗后心肌梗死面积无明显改变(P＞0.05),但左室功能显著改善(P＜0.05),左心室肥大减轻(P＜0.01),非梗死区心肌HYP含量和TGF-β_1表达降低(P＜0.05)。
结论:曲尼司特可下调MI大鼠非梗死区心肌TGF-β_1表达及降低HYP含量,减轻MI后左室非梗死区心肌纤维化,改善心脏功能。
通过以上实验研究,我们对MI后LVR过程中TGF-β_1表达和MF的形态学改变以及曲尼司特对MI后TGF-β_1表达及MF的影响有了进一步的认识。本实验首次将曲尼司特应用于大鼠MI模型中,同时对TGF-β_1表达的变化进行了观察,为MI后发生LVR和MF的防治探索新的药物治疗途径。
Left ventricular remodeling (LVR) is the process by which ventricular size, shape, and function are regulated by mechanical, neurohormonal, and genetic factors after myocardial infarction (MI). Myocardial fibrosis (MF) is a characteristic feature of LVR that is directly related to myocardial hypertrophy and heart failure (HF). According to the clinical studies, LVR process affects the short-term and long-term prognosis of MI. Cytokine transforming growth factor-β_1 (TGF-β_1) can promote the deposition of extracellular matrix (ECM), which is believed to have essential role in the process of fibrosis. Tranilast (N-[3,4-dimethoxycinnamoyl] anthranilic acid), a drug originally used for treatment of allergic and dermatological diseases, was found to inhibit TGF-β_1-madiated collagen formation. In some experimental animal studies, tranilast has been shown to reduce pathological collagen accumulation in the myocardium of hypertensive rat.
Based on the anti-TGF-β_1-madiated fibrosis mechanism of tranilast, the following experimental study is designed. The objective is to observe the effect of tranilast on myocardial fibrosis and expression of transforming growth factor-β_1 protein in the non-infarcted myocardium after myocardial infarction in rats.
MI model was established in male Wister rats by ligation of left anterior descending coronary artery. Forty-eight hours after the procedure, the survived rats were randomly divided into three groups: sham-operated group (n=10), MI model group (n=12) and Tranilast treatment group (n=13). Sham-operated rat only undergo pericardiotomy without coronary artery ligation. Rats of tranilast treatment group received a daily dose of 400mg/kg by intragastric administration in normal saline administered as 200mg/kg twice daily while untreated rats were gavaged with vehicle. After 4 weeks of treatment, the cardiac function was assessed by hemodynamic measurements before the rats were sacrificed, and left ventricular weight was measured. The heart histology and morphology was observed with HE stain. Infarct size in the infarct region was measured with previous experimental method. The expression of TGF-β_1 was detected by immunohistochemical technique. The hydroxyproline level of left ventricle non-infarcted area was measured by chloramines T method.
Result showed that compared with sham-operated rats, the left ventricular end-diastolic pressure (LVEDP), the ratio of left ventricular weight and body weight, TGF-β_1 expression and hydroxyproline level in MI model group were significantly increased (all P< 0.01), while the LV systolic pressure (LVSP), the maximum left ventricular pressure rising and dropping rates (±dP/dt) were significantly reduced (all P < 0.01). Compared with the MI model group, tranilast did not decrease infarct size (P > 0.05), but it did decrease LVEDP, the ratio of left ventricular weight and body weight, TGF-β1 expression and HYP level (P < 0.05), and increased±dP/dt significantly (P < 0.05). These results showed tranilast can inhibit myocardial fibrosis through decreasing the expression of TGF-β_1, and improve left ventricular function after MI in rats.
From this study, we could have a deeper understanding about the effect of tranilast on myocardial fibrosis and expression of TGF-β_1 after MI in rats. In conclusion, our researches can offer some referenced and theoretic proof for the clinic use which target tranilast.
目的:基于曲尼司特抑制TGF-β_1和抗纤维化的作用,本实验应用抗纤维化药物曲尼司特治疗MI大鼠,观察曲尼司特对大鼠MI后左心室MF和TGF-β_1表达的影响。材料与方法:大鼠35只,结扎大鼠左冠状动脉前降支,造成实验性心肌梗塞,将术后48h存活的大鼠随机分成三组:曲尼司特治疗组(n=13)、MI模型组(n=12)和假手术组(n=10)。假手术组大鼠,仅做开胸,在冠状动脉相同部位穿线,不结扎;曲尼司特治疗组大鼠:灌胃给药,剂量为400 mg·kg~(-1)·d~(-1)分两次给予;其他大鼠给予等量生理盐水。术后4周,颈动脉插管八导记录仪测量血流动力学指标评价心功能。计算左心室重量与体重之比以评价心室肥大情况。HE染色观察心肌组织形态学变化并计算梗死面积。免疫组化方法检测TGF-β_1的表达,氯胺T法测定左室非梗死区羟脯氨酸(HYP)含量。实验结果:与假手术组比较,MI对照组左室舒木压(LVEDP),左心室重量与体重之比,TGF-β_1的表达,羟脯氨酸含量均显著升高(P均＜0.01),而左室收缩压(LVSP),左室压力上升和下降最大变化速率(±dP/dt)显著下降(P＜0.01)。与MI模型组比较,曲尼司特治疗后心肌梗死面积无明显改变(P＞0.05),但左室功能显著改善(P＜0.05),左心室肥大减轻(P＜0.01),非梗死区心肌HYP含量和TGF-β_1表达降低(P＜0.05)。
结论:曲尼司特可下调MI大鼠非梗死区心肌TGF-β_1表达及降低HYP含量,减轻MI后左室非梗死区心肌纤维化,改善心脏功能。
通过以上实验研究,我们对MI后LVR过程中TGF-β_1表达和MF的形态学改变以及曲尼司特对MI后TGF-β_1表达及MF的影响有了进一步的认识。本实验首次将曲尼司特应用于大鼠MI模型中,同时对TGF-β_1表达的变化进行了观察,为MI后发生LVR和MF的防治探索新的药物治疗途径。
Left ventricular remodeling (LVR) is the process by which ventricular size, shape, and function are regulated by mechanical, neurohormonal, and genetic factors after myocardial infarction (MI). Myocardial fibrosis (MF) is a characteristic feature of LVR that is directly related to myocardial hypertrophy and heart failure (HF). According to the clinical studies, LVR process affects the short-term and long-term prognosis of MI. Cytokine transforming growth factor-β_1 (TGF-β_1) can promote the deposition of extracellular matrix (ECM), which is believed to have essential role in the process of fibrosis. Tranilast (N-[3,4-dimethoxycinnamoyl] anthranilic acid), a drug originally used for treatment of allergic and dermatological diseases, was found to inhibit TGF-β_1-madiated collagen formation. In some experimental animal studies, tranilast has been shown to reduce pathological collagen accumulation in the myocardium of hypertensive rat.
Based on the anti-TGF-β_1-madiated fibrosis mechanism of tranilast, the following experimental study is designed. The objective is to observe the effect of tranilast on myocardial fibrosis and expression of transforming growth factor-β_1 protein in the non-infarcted myocardium after myocardial infarction in rats.
MI model was established in male Wister rats by ligation of left anterior descending coronary artery. Forty-eight hours after the procedure, the survived rats were randomly divided into three groups: sham-operated group (n=10), MI model group (n=12) and Tranilast treatment group (n=13). Sham-operated rat only undergo pericardiotomy without coronary artery ligation. Rats of tranilast treatment group received a daily dose of 400mg/kg by intragastric administration in normal saline administered as 200mg/kg twice daily while untreated rats were gavaged with vehicle. After 4 weeks of treatment, the cardiac function was assessed by hemodynamic measurements before the rats were sacrificed, and left ventricular weight was measured. The heart histology and morphology was observed with HE stain. Infarct size in the infarct region was measured with previous experimental method. The expression of TGF-β_1 was detected by immunohistochemical technique. The hydroxyproline level of left ventricle non-infarcted area was measured by chloramines T method.
Result showed that compared with sham-operated rats, the left ventricular end-diastolic pressure (LVEDP), the ratio of left ventricular weight and body weight, TGF-β_1 expression and hydroxyproline level in MI model group were significantly increased (all P< 0.01), while the LV systolic pressure (LVSP), the maximum left ventricular pressure rising and dropping rates (±dP/dt) were significantly reduced (all P < 0.01). Compared with the MI model group, tranilast did not decrease infarct size (P > 0.05), but it did decrease LVEDP, the ratio of left ventricular weight and body weight, TGF-β1 expression and HYP level (P < 0.05), and increased±dP/dt significantly (P < 0.05). These results showed tranilast can inhibit myocardial fibrosis through decreasing the expression of TGF-β_1, and improve left ventricular function after MI in rats.
From this study, we could have a deeper understanding about the effect of tranilast on myocardial fibrosis and expression of TGF-β_1 after MI in rats. In conclusion, our researches can offer some referenced and theoretic proof for the clinic use which target tranilast.
引文
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