蛋白酪氨酸磷酸酶SHP-2特异性抑制剂PHPS1通过促进泡沫细胞形成加速apoE-基因敲除小鼠早期动脉粥样硬化进展

doi:10.3969/j.issn.1007-3205.2020.06.020

摘要/Abstract

摘要： 目的研究酪氨酸磷酸酶SHP-2 （Src Homology 2 Containing Protein Tyrosine Phosphatase 2，SHP-2）特异性抑制剂苯肼基吡唑啉酮磺酸盐1(phenylhydrazonopyrazolonesulfonate1,PHPS1)对apoE基因敲除小鼠（apoE-/-小鼠）动脉粥样硬化（atherosclerosis，AS）的影响作用。
方法 1.25%胆固醇高脂饲料饲养apoE-/-小鼠28只4周构建早期AS模型，随机分为对照组和PHPS1组。观察降主动脉斑块大小和细胞成分，评估斑块内信号通路及清道夫受体(scavenger receptor，SR)蛋白及mRNA的含量变化情况。氧化低密度脂蛋白（oxidized low-density lipoprotein，ox-LDL）和绿色荧光微球加或不加PHPS1干预骨髓来源的巨噬细胞（bone marrow-derived macrophage，BMDM）细胞16 h，观察BMDM内绿色荧光沉积情况。
结果 PHPS1组斑块内油红O面积、斑块大小、斑块内巨噬细胞含量比对照组显著增加，差异均有统计学意义（P＜0.01）。PHPS1组巨噬细胞内部绿色荧光强度比对照组显著增加，差异有统计学意义（P＜0.01）。PHPS1组白细胞分化抗原36（cluster of differentiation 36，CD36）和SR-A1的mRNA表达量比对照组显著升高，差异均有统计学意义（P＜0.01）。PHPS1组磷酸化细胞外信号调节酶（phosphorylated extracellular-regulated kinases，p-ERK）、磷酸化磷脂酰肌醇3激酶（phosphorylated phosphatidylinositol 3-kinase，p-PI3K）、磷酸化蛋白激酶B（phosphorylated protein kinase B，p-AKT）蛋白含量比对照组显著升高，差异均有统计学意义（P＜0.01）。
结论 PHPS1主要通过激活细胞外信号调节酶及磷脂酰肌醇3激酶/蛋白激酶B信号通路，影响SR的过表达从而增加了巨噬细胞对ox-LDL的吞噬能力最终促进了泡沫细胞的形成、促进AS进展。

关键词: 动脉粥样硬化, 酪氨酸磷酸酶SHP-2, PHPS1

Abstract: Objective To investigate the effects of Src Homology 2 Containing Protein Tyrosine Phosphatase 2(SHP2)specific inhibitor phenylhydrazonopyrazolonesulfonate1(PHPS1) on the progression of AS in apoE-/- mice.
Methods Early AS model was constructed in 28 apoE-/- mice on 1.25% high-cholesterol feed for 4 weeks, and they were randomly divided into control group and PHPS1 group. The size and cell components of descending aorta plaques were observed to evaluate the changes in the contents of the signaling pathway, scavenger receptor(SR) protein and mRNA in the plaques. Oxidized low density lipoprotein(ox-LDL) and green fluorescent microspheres with or without PHPS1 intervened bone marrow-derived macrophage(BMDM)cells in 16 h, and observed green fluorescent deposition of the BMDM.
Results The area of oil red O, the size of plaques and the content of macrophages in plaques in PHPS1 group were significantly increased compared with the control group, and the differences were statistically significant(P＜0.01). The green fluorescence intensity of macrophages in PHPS1 group was significantly higher than that in the control group(P＜0.01). The mRNA expression levels of cluster of differentiation 36(CD36) and scavenger receptorA1(SRA1) in PHPS1 group were significantly higher than those in the control group, and the differences were statistically significant(P＜0.01). Phosphorylated extracellular regulated kinases(p-ERK), phosphorylated phosphatidylinositol 3-kinase(p-PI3K) and phosphorylated protein kinase B(p-AKT) in the PHPS1 group were significantly higher than those in the control group.The differences were statistically significant(P＜0.01).
Conclusion PHPS1 mainly affects the overexpression of SR through extracellular-regulated kinases and phosphatidylinositol 3-kinase/protein kinase B signaling pathways, thereby increasing the phagocytosis of ox-LDL by macrophages and ultimately promoting the formation of foam cells and the progression of AS.

Key words: atherosclerosis, tyrosine phosphatase SHP-2, PHPS1

马倩1，路永刚1，李新新1，谭鹤1，朱学灿2，帖彦清1*. 蛋白酪氨酸磷酸酶SHP-2特异性抑制剂PHPS1通过促进泡沫细胞形成加速apoE-基因敲除小鼠早期动脉粥样硬化进展[J]. 河北医科大学学报, doi: 10.3969/j.issn.1007-3205.2020.06.020.

MA Qian1, LU Yong-gang1， LI Xin-xin1, TAN He1, ZHU Xue-can2， TIE Yan-qing1*. Tyrosine phosphatase SHP-2 specific inhibitor PHPS1 accelarate the progression of AS in apoE-deficient mice by promoting foam cell formation#br#[J]. Journal of Hebei Medical University, doi: 10.3969/j.issn.1007-3205.2020.06.020.

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蛋白酪氨酸磷酸酶SHP-2特异性抑制剂PHPS1通过促进泡沫细胞形成加速apoE-基因敲除小鼠早期动脉粥样硬化进展

Tyrosine phosphatase SHP-2 specific inhibitor PHPS1 accelarate the progression of AS in apoE-deficient mice by promoting foam cell formation#br#

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