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中华口腔医学研究杂志(电子版) ›› 2022, Vol. 16 ›› Issue (01) : 12 -20. doi: 10.3877/cma.j.issn.1674-1366.2022.01.003

论著

雷帕霉素通过促进细胞自噬抑制大鼠血管平滑肌细胞增殖活性效应
邬文莉1, 卢志远1, 黎凡1, 王洪涛1, 郝建锁1, 高梓君1, 陈亦阳1,†()   
  1. 1. 广州市妇女儿童医疗中心口腔颌面外科，广州　510623
  • 收稿日期:2021-11-22 出版日期:2022-02-01
  • 通信作者: 陈亦阳

Rapamycin inhibits proliferation of rat vascular smooth muscle cells by promoting autophagy

Wenli Wu1, Zhiyuan Lu1, Fan Li1, Hongtao Wang1, Jiansuo Hao1, Zijun Gao1, Yiyang Chen1,†()   

  1. 1. Department of Oral and Maxillofacial Surgery, Stomatology Medical Center, Guangzhou Women and Children′s Medical Center, Guangzhou 510623, China
  • Received:2021-11-22 Published:2022-02-01
  • Corresponding author: Yiyang Chen
  • Supported by:
    Research Fund of Guangzhou Women and Children′s Medical Center(YIP-2019-038)
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引用本文：

邬文莉, 卢志远, 黎凡, 王洪涛, 郝建锁, 高梓君, 陈亦阳. 雷帕霉素通过促进细胞自噬抑制大鼠血管平滑肌细胞增殖活性效应[J]. 中华口腔医学研究杂志(电子版), 2022, 16(01): 12-20.

Wenli Wu, Zhiyuan Lu, Fan Li, Hongtao Wang, Jiansuo Hao, Zijun Gao, Yiyang Chen. Rapamycin inhibits proliferation of rat vascular smooth muscle cells by promoting autophagy[J]. Chinese Journal of Stomatological Research(Electronic Edition), 2022, 16(01): 12-20.

目的

探讨雷帕霉素（RAP）抑制表现异常增殖活性的大鼠血管平滑肌细胞（VSMC）增殖活性的作用及其分子机制。

方法

使用不同质量浓度的血小板衍生生长因子（PDGF）作为诱导剂处理大鼠主动脉VSMC，构建模拟脉管畸形的体外模型。实验分为对照组、PDGF组、PDGF+RAP组和PDGF+VEC（血管内皮细胞）组，观察对VSMC增殖活性的改变，检测不同处理方式对VSMC自噬水平的影响。两组间比较应用独立样本t检验，多组间比较应用重复测量方差分析，多组mRNA表达量、蛋白表达量比较应用单因素方差分析。

结果

细胞增殖检测（CCK-8）和EdU实验结果显示：PDGF处理的VSMC活性呈时间依赖性上升。与PDGF组相比，在48和72 h，PDGF+RAP组细胞增殖活性分别降低了24.8%（0.129 ± 0.010比0.172 ± 0.012，t = 4.787，P = 0.009）和45.1%（0.170 ± 0.012比0.292 ± 0.046，t = 4.431，P = 0.011）；PDGF+VEC组细胞增殖活性分别降低了10.0%（0.155 ± 0.013比0.172 ± 0.012，t = 2.357，P = 0.076）和8.9%（0.266 ± 0.022比0.292 ± 0.046，t = 1.718，P = 0.161）。实时荧光定量PCR和蛋白免疫印迹（Western blot）结果显示，与对照组比较，PDGF可抑制平滑肌蛋白抗体-B（Smoothelin-B）表达（0.486 ± 0.057比1.005 ± 0.067，t = 10.192，P = 0.001），促进细胞视黄醇结合蛋白-1（CRBP-1）表达（3.185 ± 0.091比0.991 ± 0.056，t = 35.461，P<0.001）；而在PDGF+RAP组和PDGF+VEC组，Smoothelin-B表达增加（0.857 ± 0.091比0.486 ± 0.057，t = 5.943，P = 0.004；0.563 ± 0.067比0.486 ± 0.057，t = 1.501，P = 0.208），CRBP-1表达减少（1.579 ± 0.042比3.185 ± 0.091，t = 27.707，P<0.001；2.951 ± 0.144比3.185 ± 0.091，t = 2.382，P = 0.076）。与对照组比较，PDGF组LC3B（LC3-Ⅱ/Ⅰ比值）明显下降（0.175 ± 0.003比1.020 ± 0.020，t = 72.263，P<0.001），p62表达显著上升（2.632 ± 0.098比1.005 ± 0.007，t = 28.562，P = 0.001）。与PDGF组比较，PDGF+RAP组的LC3B明显升高（0.316 ± 0.037比0.175 ± 0.003，t = 6.529，P = 0.022），p62蛋白显著降低（1.396 ± 0.070比2.632 ± 0.098，t = 17.771，P<0.001）；PDGF+VEC组LC3B稍有上升（0.206 ± 0.014比0.175 ± 0.003，t = 3.687，P = 0.021），而p62蛋白表达降低（2.400 ± 0.076比2.632 ± 0.098，t = 3.220，P = 0.032）。透射电镜观察发现，PDGF+RAP组、PDGF+VEC组自噬小体较PDGF组上升。

结论

高质量浓度PDGF可使VSMC增殖活性上升；雷帕霉素或VEC可通过激活自噬，抑制PI3K/AKT信号通路使细胞活性降低，并促使VSMC向收缩型转变，逆转PDGF的效应。

关键词: 西罗莫司（雷帕霉素）, 脉管畸形, 自噬, 哺乳动物雷帕霉素靶蛋白
Objective

To investigate the effect and molecular mechanism of rapamycin (RAP) on inhibiting the proliferation of rat vascular smooth muscle cells (VSMCs) with abnormal proliferation activity.

Methods

Rat aortic VSMCs were treated with different concentrations of platelet-derived growth factor (PDGF) as an inducer to construct an in vitro model of vascular malformation. They were divided into Blank group, PDGF group, PDGF+RAP group and PDGF+VECs (vascular endothelial cells) group. The changes in the proliferation activity of VSMCs were observed and the effects of different treatments on the autophagy level of VSMCs were detected. The independent sample t test was used for comparison between two groups and the repeated measures analysis of variance was used for comparison among multiple groups. The mRNA and protein expression among multiple groups were compared via One-Way analysis of variance.

Results

The results of CCK-8 and EdU experiments showed that the activity of VSMCs treated with PDGF significantly increased in a time-dependent manner. Compared with the PDGF group, at 48 and 72 hours, the cell proliferation activity of the PDGF+RAP group was reduced by 24.8% (0.129 ± 0.010 vs. 0.172 ± 0.012, t = 4.787, P = 0.009) and 45.1% (0.170 ± 0.012 vs. 0.292 ± 0.046, t = 4.431, P = 0.011) , respectively. The cell proliferation activity of PDGF+VECs group decreased by 10.0% (0.155 ± 0.013 vs. 0.172 ± 0.012, t = 2.357, P = 0.076) and 8.9% (0.266 ± 0.022 vs. 0.292 ± 0.046, t = 1.718, P = 0.161) , respectively. Real-time quantitative PCR and Western blot results showed that, compared with the Blank group, PDGF could inhibit the expression of Smoothelin-B (0.486 ± 0.057 vs. 1.005 ± 0.067, t = 10.192, P = 0.001) and promote the expression of cellular retinol binding protein-1 (CRBP-1) (3.185 ± 0.091 vs. 0.991 ± 0.056, t = 35.461, P<0.001) . In the PDGF+RAP group and PDGF+VECs group, the expression of Smoothelin-B increased (0.857 ± 0.091 vs. 0.486 ± 0.057, t = 5.943, P = 0.004; 0.563 ± 0.067 vs. 0.486 ± 0.057, t = 1.501, P = 0.208) and the expression of CRBP-1 decreased (1.579 ± 0.042 vs. 3.185 ± 0.091, t = 27.707, P<0.001; 2.951 ± 0.144 vs 3.185 ± 0.091, t = 2.382, P = 0.076) . Compared with the Blank group, the expression of LC3B (LC3-Ⅱ/Ⅰ) in PDGF group significantly decreased (0.175 ± 0.003 vs. 1.020 ± 0.020, t = 72.263, P<0.001) , and the expression of p62 significantly increased (2.632 ± 0.098 vs. 1.005 ± 0.007, t = 28.562, P = 0.001) . Compared with PDGF group, the expression of LC3B in PDGF+RAP group significantly increased (0.316 ± 0.037 vs. 0.175 ± 0.003, t = 6.529, P = 0.022) , and the relative expression of p62 significantly decreased (1.396 ± 0.070 vs. 2.632 ± 0.098, t = 17.771, P<0.001) . The expression of LC3B in the PDGF+VECs group slightly increased (0.206 ± 0.014 vs. 0.175 ± 0.003, t = 3.687, P = 0.021) , while the expression of p62 slightly reduced (2.400 ± 0.076 vs. 2.632 ± 0.098, t = 3.220, P = 0.032) . Transmission electron microscope observation showed that autophagosomes in PDGF+RAP group and PDGF+VECs group were higher than those in PDGF group.

Conclusions

High concentration of PDGF can increase the proliferation activity of VSMCs. RAP or VECs can reduce the cell activity of VSMCs by activating autophagy and inhibiting the PI3K/AKT signaling pathway. Moreover, RAP or VECs can also promote the transformation of VSMCs to contractile phenotype as well as reverse the effect of PDGF.

Key words: Sirolimus (Rapamycin), Vascular malformation, Autophagy, Mammalian target of rapamycin
图1 血小板衍生生长因子（PDGF）通过抑制自噬激活PI3K/AKT通路促进大鼠血管平滑肌细胞（VSMC）增殖CCK-8细胞增殖活性实验结果
表1 不同质量浓度血小板衍生生长因子（PDGF）处理不同时间后大鼠血管平滑肌细胞（VSMC）活性比较（ ± s）
时间（h） 0 ng/mL 5 ng/mL 10 ng/mL 15 ng/mL 20 ng/mL 30 ng/mL
0 0.034 ± 0.006 0.044 ± 0.004 0.055 ± 0.007 0.059 ± 0.004 0.041 ± 0.009 0.049 ± 0.011
24 0.014 ± 0.005 0.020 ± 0.011 0.046 ± 0.002 0.095 ± 0.007 0.099 ± 0.015 0.107 ± 0.012
48 0.059 ± 0.011 0.038 ± 0.004 0.083 ± 0.005 0.161 ± 0.017 0.195 ± 0.023 0.209 ± 0.010
72 0.096 ± 0.003 0.065 ± 0.005 0.142 ± 0.005 0.234 ± 0.017 0.302 ± 0.033 0.317 ± 0.011
图2 血小板衍生生长因子（PDGF）通过抑制自噬激活PI3K/AKT通路促进大鼠血管平滑肌细胞（VSMC）增殖　A为EdU细胞增殖检测：随着PDGF质量浓度梯度上升，VSMC增殖活性显著增强；B为透射电镜观察：随着PDGF质量浓度梯度上升，细胞内自噬小体数目呈减少趋势。
图3 血小板衍生生长因子（PDGF）通过抑制自噬激活PI3K/AKT通路促进大鼠血管平滑肌细胞（VSMC）增殖实时荧光定量PCR实验结果　 aP<0.05；bP<0.001。
表2 不同质量浓度血小板衍生生长因子（PDGF）处理大鼠血管平滑肌细胞（VSMC）的Smoothelin-B、CRBP-1表达量变化（ ± s）
标记物 0 ng/mL 5 ng/mL 10 ng/mL 15 ng/mL 20 ng/mL F值 P值
Smoothelin-B 1.005 ± 0.125 1.161 ± 0.081 0.773 ± 0.079 0.430 ± 0.035 0.319 ± 0.028 64.07 0.000
CRBP-1 1.001 ± 0.049 1.223 ± 0.013 1.851 ± 0.103 2.156 ± 0.127 2.449 ± 0.170 96.63 0.000
图4 血小板衍生生长因子（PDGF）通过抑制自噬激活PI3K/AKT通路促进大鼠血管平滑肌细胞（VSMC）增殖的Western blot检测
表3 不同质量浓度血小板衍生生长因子（PDGF）处理大鼠血管平滑肌细胞（VSMC）的后相关蛋白表达量变化（ ± s）
标记物 0 ng/mL 5 ng/mL 10 ng/mL 15 ng/mL 20 ng/mL F值 P值
Smoothelin-B 1.027 ± 0.029 0.936 ± 0.030 0.653 ± 0.002 0.358 ± 0.004 0.238 ± 0.004 1017.677 0.000
CRBP-1 1.018 ± 0.018 1.048 ± 0.016 1.579 ± 0.041 1.804 ± 0.046 2.767 ± 0.082 684.959 0.000
PI3K 1.005 ± 0.006 1.010 ± 0.005 1.005 ± 0.022 1.044 ± 0.012 1.000 ± 0.059 1.188 0.374
AKT 1.020 ± 0.026 1.000 ± 0.020 1.015 ± 0.045 1.005 ± 0.049 1.006 ± 0.027 0.200 0.933
mTOR 0.985 ± 0.029 0.999 ± 0.017 0.971 ± 0.018 0.994 ± 0.044 1.000 ± 0.078 0.231 0.915
p-PI3K 1.018 ± 0.022 0.924 ± 0.064 1.990 ± 0.045 2.961 ± 0.057 3.922 ± 0.077 1557.287 0.000
P-AKT 1.007 ± 0.007 1.267 ± 0.089 1.663 ± 0.097 2.680 ± 0.050 3.333 ± 0.211 225.198 0.000
p-mTOR 1.017 ± 0.020 0.945 ± 0.012 1.837 ± 0.071 2.444 ± 0.085 3.055 ± 0.072 690.421 0.000
LC3B 1.013 ± 0.021 0.759 ± 0.034 0.642 ± 0.018 0.301 ± 0.037 0.195 ± 0.022 677.950 0.000
p62 1.013 ± 0.016 1.782 ± 0.051 2.577 ± 0.088 3.576 ± 0.078 3.480 ± 0.100 446.504 0.000
图5 雷帕霉素或血管内皮细胞（VEC）对血小板衍生生长因子（PDGF）诱导的大鼠血管平滑肌细胞（VSMC）活性效应的影响CCK-8细胞增殖实验结果
表4 不同实验组处理大鼠血管平滑肌细胞（VSMC）的细胞活性差异（ ± s）
组别 0 h 24 h 48 h 72 h
对照组 0.040 ± 0.017 0.052 ± 0.018 0.079 ± 0.003 0.126 ± 0.010
PDGF组 0.017 ± 0.008 0.097 ± 0.009 0.172 ± 0.012 0.292 ± 0.046
PDGF+RAP组 0.010 ± 0.006 0.092 ± 0.012 0.129 ± 0.010 0.170 ± 0.012
PDGF+VEC组 0.037 ± 0.019 0.084 ± 0.004 0.155 ± 0.013 0.266 ± 0.022
图6 雷帕霉素或血管内皮细胞（VEC）对血小板衍生生长因子（PDGF）诱导的大鼠血管平滑肌细胞（VSMC）活性效应的影响EdU细胞增殖检测结果
图7 雷帕霉素或血管内皮细胞（VEC）对血小板衍生生长因子（PDGF）诱导的PI3K/AKT信号通路激活效应影响的实时荧光定量PCR实验结果　 aP<0.01。
表5 不同实验组处理大鼠血管平滑肌细胞（VSMC）后Smoothelin-B、CRBP-1的相对表达量结果（ ± s）
标记物 对照组 PDGF组 PDGF+RAP组 PDGF+VEC组 F值 P值
Smoothelin-B 1.005 ± 0.067 0.486 ± 0.057 0.857 ± 0.091 0.563 ± 0.067 34.689 0.000
CRBP-1 0.991 ± 0.056 3.185 ± 0.091 1.579 ± 0.042 2.951 ± 0.144 399.591 0.000
图8 雷帕霉素或血管内皮细胞（VEC）对血小板衍生生长因子（PDGF）诱导的PI3K/AKT信号通路激活效应影响的Western blot结果
表6 雷帕霉素或血管内皮细胞（VEC）对血小板衍生生长因子（PDGF）诱导的PI3K/AKT信号通路激活效应的影响（ ± s）
标记物 对照组 PDGF组 PDGF+RAP组 PDGF+VEC组 F值 P值
Smoothelin-B 1.005 ± 0.007 0.329 ± 0.015 0.619 ± 0.034 0.722 ± 0.027 431.684 0.000
CRBP-1 1.006 ± 0.007 2.745 ± 0.080 1.567 ± 0.065 1.961 ± 0.059 452.206 0.000
PI3K 1.004 ± 0.006 0.989 ± 0.033 1.024 ± 0.079 1.027 ± 0.020 0.490 0.699
AKT 1.023 ± 0.020 0.975 ± 0.051 0.933 ± 0.073 0.973 ± 0.039 1.650 0.254
mTOR 1.019 ± 0.023 1.018 ± 0.022 0.962 ± 0.060 0.978 ± 0.014 2.071 0.183
p-PI3K 1.008 ± 0.013 3.450 ± 0.233 2.199 ± 0.181 2.558 ± 0.138 115.444 0.000
P-AKT 1.013 ± 0.016 2.773 ± 0.062 1.341 ± 0.055 1.915 ± 0.075 564.555 0.000
p-mTOR 1.008 ± 0.013 2.573 ± 0.077 1.346 ± 0.068 1.628 ± 0.120 216.225 0.000
图9 雷帕霉素或血管内皮细胞（VEC）对大鼠血管平滑肌细胞（VSMC）自噬水平影响的Western blot结果
表7 雷帕霉素或血管内皮细胞（VEC）对大鼠血管平滑肌细胞（VSMC）自噬水平的影响（ ± s）
标记物 对照组 PDGF组 PDGF+RAP组 PDGF+VEC组 F值 P值
LC3B 1.020 ± 0.020 0.175 ± 0.003 0.316 ± 0.037 0.206 ± 0.014 957.549 0.000
p62 1.005 ± 0.007 2.632 ± 0.098 1.396 ± 0.070 2.400 ± 0.076 359.383 0.000
图10 雷帕霉素或血管内皮细胞（VEC）对大鼠血管平滑肌细胞（VSMC）自噬水平的影响　A：免疫荧光染色结果显示，与PDGF组比较，PDGF+RAP组及PDGF+VEC组LC3B（绿）表达升高；B：透射电镜观察，与PDGF组比较，PDGF+RAP组及PDGF+VEC组自噬小体数目恢复，PDGF的自噬抑制作用得到逆转。
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