| 史承勇,刁繁荣,蒋颖人,宋晓伟,唐文栋,郭 显,赵仙先.鞘鞍醇激酶-1抑制剂PF-543改善1型糖尿病心肌纤维化的实验研究[J].,2019,19(9):1613-1617 |
| 鞘鞍醇激酶-1抑制剂PF-543改善1型糖尿病心肌纤维化的实验研究 |
| Experimental Study of Amelioration of Cardiac Fibrosis by PF-543 in Type 1 Diabetic Mice |
| 投稿时间：2019-01-23 修订日期：2019-02-27 |
| DOI：10.13241/j.cnki.pmb.2019.09.003 |
| 中文关键词: 鞘鞍醇激酶-1 1-磷酸鞘鞍醇 PF-543 1型糖尿病 心肌纤维化 |
| 英文关键词: Sphingosine kinase-1 Sphingosine 1 phosphate PF-543 Type 1 diabetes mellitus Cardiac fibrosis |
| 基金项目:国家自然科学基金项目（81570208） |
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| 中文摘要: |
| 摘要 目的：研究鞘鞍醇激酶-1抑制剂PF-543对1型糖尿病心肌纤维化的影响及其机制。方法：取60只8周龄雄性C57BL6J小鼠，随机分为对照组、对照+PF-543组、1型糖尿病组及1型糖尿病+PF-543组。采用禁食后一次性腹腔注射链脲佐菌素（STZ，150 mg/kg）构建1型糖尿病模型。造模后每天通过腹腔注射给予溶媒或PF-543（1 mg/kg），持续至造模后第16周末。造模第16周末采用酶联免疫吸附试验（ELISA）检测心肌组织1-磷酸鞘鞍醇（S1P）浓度；采用心脏超声评估心脏收缩与舒张功能；Masson三色法染色以评估心肌纤维化情况；Western blot检测心脏转化生长因子-β1（TGF-β1）、I型胶原蛋白（Col I）、III型胶原蛋白（Col III）表达水平。结果：1型糖尿病+PF-543组小鼠血浆及心肌S1P水平显著低于1型糖尿病组（所有P＜0.05）。超声结果显示，1型糖尿病+PF-543组小鼠心脏左心室射血分数（LVEF）显著高于1型糖尿病组（65.7±3.3% vs 54.4±3.4%，P＜0.05），左心室舒张末期内径（LVEDD）显著小于1型糖尿病组（3.81±0.21mm vs 4.52±0.20mm，P＜0.05）。Masson三色法染色显示1型糖尿病+PF-543组心肌纤维化程度显著低于1型糖尿病组（7.13±0.32% vs 10.21±0.41%，P＜0.05）。1型糖尿病+PF-543组小鼠心脏TGF-β1、Col I与Col III蛋白表达水平均低于1型糖尿病组（所有P＜0.05）。结论：鞘鞍醇激酶-1抑制剂PF-543可显著降低1型糖尿病小鼠血浆与心脏S1P水平，降低心脏TGF-β1表达与胶原蛋白沉积，改善1型糖尿病小鼠心脏纤维化与心功能。 |
| 英文摘要: |
| ABSTRACT Objective: This study was aimed to explore the effects of PF-543, a specific inhibitor of sphingosine kinase-1 (SphK1), on cardiac fibrosis in type 1 diabetes mice. Methods: Sixty eight-week-old C57BL6J mice were randomly divided into control group(n=15), control+PF-543 group (n=15), type 1 diabetes mellitus（T1DM） group (n=15), and T1DM+PF-543 group (n=15). T1DM were in- duced by intraperitoneally injected with streptozocin (STZ, 150 mg/kg). These control and diabetic mice were randomly received with ve- hicle or PF-543 (10 mg/kg/d) treatment for 16 weeks. By the end of the study, cardiac sphingosine 1 phosphate (S1P) levels were ana- lyzed by enzyme linked immunosorbent assay (ELISA). Cardiac function was evaluated by echocardiography. Myocardial fibrosis was evaluated by masson trichrome staining. The cardiac expression levels of transforming growth factor-β1（TGF-β1）, Collagen I (Col I) and Collagen III (Col III) were determined by Western blot. Results: Compared with T1DM group, cardiac S1P levels were significantly reduced in T1DM+PF-543 group (P＜0.05). PF-543 significantly increased the left ventricular ejection fractions (LVEF) in diabetic mice (65.7±3.3% vs 54.4±3.4%, P＜0.05). PF-543 alsodecreased the left ventricular end-diastolic diameters (LVEDD) in diabetic mice (3.81±0.21 mm vs 4.52±0.20 mm P＜0.05). Moreover, PF-543 treatment reduced interstitial fibrosis in diabetic mice (7.13±0.32% vs 10.21±0.41%, P＜0.05). the cardiac expression of TGF-β1, Col I and Col III were significantly reduced by PF-543 treatment in type 1 diabetic mice (all P＜0.05). Conclusion: PF-543 treatment significantly reduces cardiac S1P levels and ameliorates myocardial fibrosis by decreasing TGF-β1 and collagen expression in type 1 diabetic mice. |
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