OPG在腹主动脉瘤中的表达及OPG与主动脉平滑肌细胞凋亡关系研究
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摘要
目的：
检测OPG(骨保护素)在不同直径大小人腹主动脉瘤(AAA)组织中的表达情况,探讨其在腹主动脉瘤发生发展过程中的作用。
方法：
(1)应用免疫组织化学方法检测20例AAA组织(包括6例小腹主动脉瘤(SAAA):横径4.0-5.5cm,6例中腹主动脉瘤(MAAA):横径5.5-7.0cm,4例大腹主动脉瘤(LAAA):横径≥7.0cm,4例破裂型腹主动脉瘤(RAAA)和对照组6例正常腹主动脉组织OPG的表达。
(2)Western-blooting和RT-PCR技术检测不同直径大小瘤体中OPG,MMP-9蛋白及mRNA表达情况。
结果：
(1)与正常腹主动脉对照,AAA组织中OPG的阳性细胞明显增多,主要分布于中膜,并与炎性细胞浸润程度呈显著正相关,AAA组中OPG的表达明显高于对照组,差异具有显著性(P<0.05)。
(2)OPG的蛋白及mRNA表达在AAA组明显高于正常腹主动脉,差异具有显著性(P<0.05),且与MMP-9表达及瘤体直径呈显著正相关。
结论：OPG水平与AAA有关,OPG可能通过促进基质金属蛋白酶的表达和炎症细胞浸润,在基质和细胞水平参与腹主动脉结构损伤与重构,促进AAA形成和发展。
目的观察兔体内主动脉壁剪切力变化情况下动脉成瘤的形态学变化及OPG的表达情况及其与中膜血管平滑肌细胞(VSMCs)密度降低的关系。
方法取新西兰兔共24只,在肾动脉平面以下2cm将供体的一段腹主动脉壁作补片移植到受体腹主动脉而成瘤,分别在术后7,21,35天获取瘤体及腹主动脉组织标本,分别测量术前及成瘤后腹主动脉的形态学参数,免疫组织化学法检测OPG抗原的表达,半定量逆转录聚合酶链反应(RT-PCR)检测OPG、MMP-9的mRNA表达,Western blot检测OPG、MMP-9的蛋白产物表达,原位末端DNA标记技术(TUNEL)测定中膜VSMCs凋亡的变化；计算机图像分析并计算VSMCs密度及平均光密度。
结果实验组兔存活15只,腹主动脉血流通畅,无吻合口狭窄,实验组腹主动脉直径随时间延长逐渐扩张,与对照组有显著差异(P 结论1血管补片法构建的AAA是一种稳定可靠的动物模型,适用于AAA发病机制及防治的体内研究。
2动脉壁剪切力变化可以引起局部OPG, MMP-9表达增加及VSMCs凋亡增加。
3 OPG表达与VSMCs凋亡具有相关性,可能对动脉瘤形成起着一定的作用。
目的：利用OPG基因过表达及RNA干扰技术作用于人主动脉血管平滑肌细胞(VSMCs),观察VSMCs凋亡的情况。
方法：①实验材料：购买OPG基因,同时体外化学合成4条OPG序列特异性小干扰RNA(small interfering RNA, siRNA)。②实验方法：将购买的OPG基因亚克隆至穿梭载体上,同时随机选择一条shRNA,构建shRNA真核表达载体,包装腺病毒,转染人主动脉VSMCs。③实验分组：分为空白组、OPG过表达组、OPG过表达+RNA干扰组。④实验评估：应用RT-PCR,Western blot检测OPG基因表达的变化；应用流式细胞仪检测VSMCs凋亡情况。
结果：①空白细胞组中,OPG表达量比较弱；OPG过表达组中,OPG表达量大大增加；OPG过表达+OPG RNA干扰组中,由于OPG表达受到抑制,OPG表达量下降较明显。②OPG过表达组的细胞凋亡率较空白细胞组有较大上升,而同时进行RNA干扰后,细胞凋亡率有一定程度下降,显示OPG的表达和VSMCs凋亡之间存在一个正比关系。
结论：RNA干扰介导的OPG基因沉寂可显著抑制VSMCs的凋亡,OPG的过表达可明显加速VSMCs的凋亡。
Objective:.
To measure the expression of osteoprotegerin(OPG) in human abdominal aortic aneurysm(AAA) of various diameters, investigate it's function in the formation and development of AAA
Method:
(1) Immunohistochemistry was applied to detect the expressions of OPG in the tissue specimens of 20 AAA tissues of various diameters(6 small AAA:4.0-5.5cm,6 moderate-diameter AAA:5.5-7.0cm,4 large AAA:≥7.0cm and 4 ruptured AAA(RAAA) and 6 cases of normal human abdominal aorta in the control group.
(2) Western-blot and RT-PCR was applied to detect the protein and RNA expression of OPG and MMP-9 in various diameters AAA.
Result:
(1) OPG mainly expressed in the media of AAA compare with normal abdominal aorta, and strongly correlated with inflammatory cells infiltration. The expression of OPG in AAA group is much higher than control group(P<0.05).
(2) Western analysis and RT-PCR showed greater OPG concentrations in AAA biopsies compared with biopsies of normal aorta(P<0.05), and the expression of OPG was strongly correlated with aneurysm growth and expression of MMP-9.
Conclusion:
The findings of our study support an association between OPG and human abdominal aortic aneurysm growth, it demonstrating a possible feasible active role for OPG in the progression of AAA by means of stimulates MMP-9 activity and inflammatory cells infiltration.
Objective To observe the morphological change of aortic aneurysm in rabbit and the expression of OPG in condition that local arterial wall shear stress is changed.
Methods The animal model was created by the removal of abdominal aorta below the renal artery of donor rabbit and made a patch on the suprarenal abdominal aorta of receptor rabbit, The arterial wall below and above the patch was harvest after 7days,21 day,35days respectively. The morphological parameter of abdominal aorta was measured before operation and after operation. The level change of OPG was observed by immunohistochemistry. RT-PCR and Western-blot was applied to detect the RNA and protein expression of OPG and MMP-9 in different group. The apoptosis of VSMCs was measured by TUNEL
Results The blood flow was unobstructed in the abdominal aortic aneurysm of 83% survival receptor, no stenosis in stoma. The diameter of aneurysm was gradually increased as time goes by within 2 weeks(P<0.05). The content of elastin, collagen fibers and SMC in media was in a negative correlation mode with the diameter of aneurysm (P<0.05). The immunohistochemical staining showed that the expression of OPG in experiment group was higher than normal group (P<0.05) and strongly correlated with the diameter of AAA. RT-PCR and Western-blot showed greater OPG and MMP-9 concentrations in experiment group compared with normal group, and the expression of OPG was strongly correlated with aneurysm growth. TUNEL positive cells was detected much more in experiment group than normal group and have positive correlated with aneurysm growth.
Conclusion
1 The change of wall shear stress after the transplantation of a patch into rabbit abdominal aorta could induce AAA formation with high incidence and stability, which applies to further studies of AAA pathogenesis and prevention and cure in vivo.
2 The change of local arterial wall shear stress can upregulate the expression of OPG, MMP-9 as well as the apoptosis of VSMCs.
3 The expression of OPG may be have some relevance with apoptosis of VSMCs, which involved in the progression of aneurysm.
Object:To investigate the effects on the apoptosis of human vascular smooth cells (hVSMCs) after silencing the OPG with specific siRNA and OPG gene over-expression.
Method:OPG was subcloned into adenovirus vector to construct recombinant adenovirus, together with chemically synthesized targeted for OPG gene double-stranded siRNA were transfected into VSMCs.The expression of OPG mRNA was identified by RT-PCR and Western blot,respectively. The apoptosis of VSMCs was examined by FACS.
Results:The pshRNA-OPG may inhibit the expression of OPG gene at the levels of transcription and translation. There were significant differences of the expression of OPG mRNA between the VSMCs that were transfected with pshRNA-OPG and the ones in over-expression group and control group, respectively. The apoptosis of VSMCs was be markedly increased in the OPG over-expression group than control group, while inhibit apoptosis in RNAi group. There is a positve relationship between expression of OPG and apoptosis of VSMCs.
Conclusion:The adenovirus containing the small interference RNA of OPG may have an inhibitory effects on the apoptosis and endogenous expression of OPG gene at the levels of transcription in VSMCs. And the OPG gene over-expression may promote the apoptosis of VSMCs.
检测OPG(骨保护素)在不同直径大小人腹主动脉瘤(AAA)组织中的表达情况,探讨其在腹主动脉瘤发生发展过程中的作用。
方法：
(1)应用免疫组织化学方法检测20例AAA组织(包括6例小腹主动脉瘤(SAAA):横径4.0-5.5cm,6例中腹主动脉瘤(MAAA):横径5.5-7.0cm,4例大腹主动脉瘤(LAAA):横径≥7.0cm,4例破裂型腹主动脉瘤(RAAA)和对照组6例正常腹主动脉组织OPG的表达。
(2)Western-blooting和RT-PCR技术检测不同直径大小瘤体中OPG,MMP-9蛋白及mRNA表达情况。
结果：
(1)与正常腹主动脉对照,AAA组织中OPG的阳性细胞明显增多,主要分布于中膜,并与炎性细胞浸润程度呈显著正相关,AAA组中OPG的表达明显高于对照组,差异具有显著性(P<0.05)。
(2)OPG的蛋白及mRNA表达在AAA组明显高于正常腹主动脉,差异具有显著性(P<0.05),且与MMP-9表达及瘤体直径呈显著正相关。
结论：OPG水平与AAA有关,OPG可能通过促进基质金属蛋白酶的表达和炎症细胞浸润,在基质和细胞水平参与腹主动脉结构损伤与重构,促进AAA形成和发展。
目的观察兔体内主动脉壁剪切力变化情况下动脉成瘤的形态学变化及OPG的表达情况及其与中膜血管平滑肌细胞(VSMCs)密度降低的关系。
方法取新西兰兔共24只,在肾动脉平面以下2cm将供体的一段腹主动脉壁作补片移植到受体腹主动脉而成瘤,分别在术后7,21,35天获取瘤体及腹主动脉组织标本,分别测量术前及成瘤后腹主动脉的形态学参数,免疫组织化学法检测OPG抗原的表达,半定量逆转录聚合酶链反应(RT-PCR)检测OPG、MMP-9的mRNA表达,Western blot检测OPG、MMP-9的蛋白产物表达,原位末端DNA标记技术(TUNEL)测定中膜VSMCs凋亡的变化；计算机图像分析并计算VSMCs密度及平均光密度。
结果实验组兔存活15只,腹主动脉血流通畅,无吻合口狭窄,实验组腹主动脉直径随时间延长逐渐扩张,与对照组有显著差异(P
2动脉壁剪切力变化可以引起局部OPG, MMP-9表达增加及VSMCs凋亡增加。
3 OPG表达与VSMCs凋亡具有相关性,可能对动脉瘤形成起着一定的作用。
目的：利用OPG基因过表达及RNA干扰技术作用于人主动脉血管平滑肌细胞(VSMCs),观察VSMCs凋亡的情况。
方法：①实验材料：购买OPG基因,同时体外化学合成4条OPG序列特异性小干扰RNA(small interfering RNA, siRNA)。②实验方法：将购买的OPG基因亚克隆至穿梭载体上,同时随机选择一条shRNA,构建shRNA真核表达载体,包装腺病毒,转染人主动脉VSMCs。③实验分组：分为空白组、OPG过表达组、OPG过表达+RNA干扰组。④实验评估：应用RT-PCR,Western blot检测OPG基因表达的变化；应用流式细胞仪检测VSMCs凋亡情况。
结果：①空白细胞组中,OPG表达量比较弱；OPG过表达组中,OPG表达量大大增加；OPG过表达+OPG RNA干扰组中,由于OPG表达受到抑制,OPG表达量下降较明显。②OPG过表达组的细胞凋亡率较空白细胞组有较大上升,而同时进行RNA干扰后,细胞凋亡率有一定程度下降,显示OPG的表达和VSMCs凋亡之间存在一个正比关系。
结论：RNA干扰介导的OPG基因沉寂可显著抑制VSMCs的凋亡,OPG的过表达可明显加速VSMCs的凋亡。
Objective:.
To measure the expression of osteoprotegerin(OPG) in human abdominal aortic aneurysm(AAA) of various diameters, investigate it's function in the formation and development of AAA
Method:
(1) Immunohistochemistry was applied to detect the expressions of OPG in the tissue specimens of 20 AAA tissues of various diameters(6 small AAA:4.0-5.5cm,6 moderate-diameter AAA:5.5-7.0cm,4 large AAA:≥7.0cm and 4 ruptured AAA(RAAA) and 6 cases of normal human abdominal aorta in the control group.
(2) Western-blot and RT-PCR was applied to detect the protein and RNA expression of OPG and MMP-9 in various diameters AAA.
Result:
(1) OPG mainly expressed in the media of AAA compare with normal abdominal aorta, and strongly correlated with inflammatory cells infiltration. The expression of OPG in AAA group is much higher than control group(P<0.05).
(2) Western analysis and RT-PCR showed greater OPG concentrations in AAA biopsies compared with biopsies of normal aorta(P<0.05), and the expression of OPG was strongly correlated with aneurysm growth and expression of MMP-9.
Conclusion:
The findings of our study support an association between OPG and human abdominal aortic aneurysm growth, it demonstrating a possible feasible active role for OPG in the progression of AAA by means of stimulates MMP-9 activity and inflammatory cells infiltration.
Objective To observe the morphological change of aortic aneurysm in rabbit and the expression of OPG in condition that local arterial wall shear stress is changed.
Methods The animal model was created by the removal of abdominal aorta below the renal artery of donor rabbit and made a patch on the suprarenal abdominal aorta of receptor rabbit, The arterial wall below and above the patch was harvest after 7days,21 day,35days respectively. The morphological parameter of abdominal aorta was measured before operation and after operation. The level change of OPG was observed by immunohistochemistry. RT-PCR and Western-blot was applied to detect the RNA and protein expression of OPG and MMP-9 in different group. The apoptosis of VSMCs was measured by TUNEL
Results The blood flow was unobstructed in the abdominal aortic aneurysm of 83% survival receptor, no stenosis in stoma. The diameter of aneurysm was gradually increased as time goes by within 2 weeks(P<0.05). The content of elastin, collagen fibers and SMC in media was in a negative correlation mode with the diameter of aneurysm (P<0.05). The immunohistochemical staining showed that the expression of OPG in experiment group was higher than normal group (P<0.05) and strongly correlated with the diameter of AAA. RT-PCR and Western-blot showed greater OPG and MMP-9 concentrations in experiment group compared with normal group, and the expression of OPG was strongly correlated with aneurysm growth. TUNEL positive cells was detected much more in experiment group than normal group and have positive correlated with aneurysm growth.
Conclusion
1 The change of wall shear stress after the transplantation of a patch into rabbit abdominal aorta could induce AAA formation with high incidence and stability, which applies to further studies of AAA pathogenesis and prevention and cure in vivo.
2 The change of local arterial wall shear stress can upregulate the expression of OPG, MMP-9 as well as the apoptosis of VSMCs.
3 The expression of OPG may be have some relevance with apoptosis of VSMCs, which involved in the progression of aneurysm.
Object:To investigate the effects on the apoptosis of human vascular smooth cells (hVSMCs) after silencing the OPG with specific siRNA and OPG gene over-expression.
Method:OPG was subcloned into adenovirus vector to construct recombinant adenovirus, together with chemically synthesized targeted for OPG gene double-stranded siRNA were transfected into VSMCs.The expression of OPG mRNA was identified by RT-PCR and Western blot,respectively. The apoptosis of VSMCs was examined by FACS.
Results:The pshRNA-OPG may inhibit the expression of OPG gene at the levels of transcription and translation. There were significant differences of the expression of OPG mRNA between the VSMCs that were transfected with pshRNA-OPG and the ones in over-expression group and control group, respectively. The apoptosis of VSMCs was be markedly increased in the OPG over-expression group than control group, while inhibit apoptosis in RNAi group. There is a positve relationship between expression of OPG and apoptosis of VSMCs.
Conclusion:The adenovirus containing the small interference RNA of OPG may have an inhibitory effects on the apoptosis and endogenous expression of OPG gene at the levels of transcription in VSMCs. And the OPG gene over-expression may promote the apoptosis of VSMCs.
引文
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