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Year : 2018  |  Volume : 131  |  Issue : 14  |  Page : 1715-1723

Inhibitory Effects of Sulfur Dioxide on Rat Myocardial Fibroblast Proliferation and Migration

1 Department of Pediatrics, Peking University First Hospital, Beijing 100034, China
2 Department of Pediatrics, Peking University First Hospital; Division of Small Molecules and Cardiovascular Disease, Key Laboratory of Molecular Cardiology, Ministry of Education, Beijing 100083, China
3 Department of Physiology and Pathophysiology, Peking University Health Science Centre, Beijing 100091, China

Correspondence Address:
Prof. Ya-Qian Huang
Department of Pediatrics, Peking University First Hospital, Xi-An Men Str. No. 1, West District, Beijing 100034
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0366-6999.235875

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Background: Myocardial fibrosis is an important pathological change in many heart diseases, but its pathogenesis is very complex and has not yet been fully elucidated. The study was designed to examine whether endogenous sulfur dioxide (SO2) is a novel myocardial fibroblast proliferation and migration inhibitor. Methods: Primary rat myocardial fibroblasts were isolated and transfected with aspartate aminotransferase (AAT1 and AAT2) knockdown lentivirus or empty lentivirus. SO2 content in the supernatant was determined with high-performance liquid chromatography, and the expressions of AAT1, AAT2, proliferating cell nuclear antigen (PCNA), phosphorylated extracellular signal-regulated protein kinase (p-ERK), and total ERK (T-ERK) in the cells were detected. Cell migration was detected by wound healing test. Independent sample t-test (for two groups) and one-way analysis of variance (three or more groups) were used to analyze the results. Results: Both AAT1 and AAT2 knockdown significantly reduced SO2levels (F = 31.46, P < 0.01) and AAT1/2 protein expression (AAT1, t = 12.67, P < 0.01; AAT2, t = 9.61, P < 0.01), but increased PCNA expression and Cell Counting Kit-8 (CCK-8) activity as well as the migration in rat primary myocardial fibroblasts (P < 0.01). Supplementation of SO2rather than pyruvate significantly inhibited the increase in proliferation and migration caused by AAT knockdown (P < 0.01). Mechanistically, the ratio of p-ERK to T-ERK was significantly increased in the AAT1/2 knockdown groups compared with that in the empty lentivirus group (AAT1, t = −7.36, P < 0.01; AAT2, t = −10.97, P < 0.01). Whereas PD98059, an inhibitor of ERK activation, successfully blocked AAT knockdown-induced PCNA upregulation (F = 74.01, P > 0.05), CCK-8 activation (F = 50.14, P > 0.05), and migration augmentation in myocardial fibroblasts (24 h, F = 37.08, P > 0.05; 48 h, F = 58.60, P > 0.05). Conclusion: Endogenous SO2might be a novel myocardial fibroblast proliferation and migration inhibitor via inhibiting the ERK signaling pathway.


 Abstract in Chinese



背景:心肌纤维化是许多心脏疾病的重要病理变化,但其发病机制非常复杂,目前尚未完全阐明。 该研究旨在研究内源性二氧化硫(SO2)是否是一种新型心肌成纤维细胞增殖和迁移抑制剂。

方法:分离原代大鼠心肌成纤维细胞采用天冬氨酸氨基转移酶(AAT1和AAT2)敲低的慢病毒和空慢病毒分别转染原代大鼠心肌成纤维细胞。用高效液相色谱法测定上清液中SO2含量,蛋白印迹法细胞中AAT1、AAT2、增殖细胞核抗原(PCNA)、磷酸化胞外受体激酶(p-ERK)和总ERK(T-ERK) 蛋白含量。 通过细胞划痕实验检测细胞迁移。 使用独立样本t检验(对于两组)和单因素方差分析(三个或更多组)分析结果。

结果:AAT1和AAT2敲低均显著降低SO2水平(F = 31.46,P < 0.01)和AAT1 / 2蛋白表达(AAT1,t = 12.67,P < 0.01;AAT2,t = 9.61,P < 0.01),但显著增加PCNA的蛋白表达(AAT1,F = 31.70,P <0.01;AAT2,F = 18.93,P <0.01)和CCK-8活性(F = 56.99,P < 0.01)以及大鼠原代心肌成纤维细胞的迁移(24小时,F= 53.01,P < 0.01和48小时,F = 43.35,P < 0.01)。 SO2而非丙酮酸的补充可显著抑制由AAT敲低引起的增殖和迁移的增加(P均 < 0.01)。从机制上看,AAT1 / 2敲除组p-ERK与T-ERK的比值显著高于空病毒组(AAT1,t = -7.36,P < 0.01;AAT2,t = -10.97,P < 0.01),而ERK激活的抑制剂PD98059阻断了AAT敲低诱导的PCNA上调(F = 74.01,P > 0.05)、CCK-8激活(F = 50.14,P > 0.05)以及心肌成纤维细胞迁移(24小时,F = 37.08,P > 0.05和48小时,F = 58.60,P > 0.05)。


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