CREG调控内皮细胞周期的作用机制研究及其在小鼠下肢缺血模型中的作用
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摘要
目的：
内皮损伤是动脉粥样硬化、心肌梗死、经皮冠状动脉介入治疗术后支架内再狭窄、下肢动脉硬化闭塞症（PAD）、休克等各种血栓性疾病的始动病因。促进内皮细胞（EC）的完整性，维持其正常功能，将为此类疾病提供新的防治手段。本研究探讨了一个新近发现的调控细胞转录的基因——E1A激活基因阻遏子（CREG）调控人脐静脉内皮细胞（HUVEC）周期的作用和机制，并在小鼠下肢缺血模型中初步探讨了其对血管新生的影响。
方法：
（1）以绿色荧光蛋白（GFP）腺病毒感染HUVEC作为对照，应用CREG腺病毒使HUVEC过表达CREG，以细胞计数、BrdU掺入实验、流式细胞术（FCM）检测CREG对HUVEC增殖的影响，Western blot检测HUVEC中CREG、信号通路、细胞周期蛋白（Cyclins）及细胞周期蛋白依赖性激酶（CDKs）的表达，RT-PCR检测Cyclins在转录水平上的表达差异。（2）以表达短发卡RNA （shRNA）序列的阴性空载体为对照，将CREG表达沉默的shRNA载体转染至逆转录病毒，产生病毒后感染HUVEC，经嘌呤霉素筛选，得到CREG表达下调的HUVEC；应用细胞计数、BrdU掺入实验、FCM检测从功能缺失角度验证CREG下调对HUVEC增殖的影响。（3）根据信号通路Western blot结果的提示，应用信号通路阻断剂阻断可被CREG明显影响的信号通路，以BrdU掺入实验及FCM检测细胞增殖并确定CREG发挥生物学作用的通路，Westernblot检测蛋白表达及信号通路蛋白及Cyclins的表达，确定CREG相关的信号通路及Cyclins。（4）在腺病毒感染造成CREG过表达的HUVEC中使用血管内皮生长因子中和抗体（VEGF NA）阻断VEGF的作用；在CREG被干扰造成其表达下调的HUVEC中添加重组人血管内皮生长因子（rhVEGF165），以细胞计数、BrdU掺入试验、FCM检测细胞增殖，同时以Western blot检测信号通路以及Cyclins的表达，确定血管内皮生长因子（VEGF）是否参与了CREG调控HUVEC增殖及Cyclins表达的作用。（5）以正常的以及感染GFP腺病毒的HUVEC作为对照，应用体外及小鼠在体matrigel血管生成实验检测HUVEC感染CERG腺病毒后对血管生成的影响；制作小鼠下肢缺血模型后，以PBS、GFP腺病毒做为对照，应用CREG腺病毒感染局部缺血肌肉组织，观测术肢体温、自体截肢率，以病理切片观测肌纤维形态改变，应用血流灌注成像仪检测术肢/健肢灌注比，检测CREG对小鼠下肢缺血的治疗作用以及对血管新生的影响。
结果：
（1）与对照组相比，HUVEC经腺病毒感染过表达CREG后，细胞计数增多，BrdU掺入实验中BrdU阳性细胞百分比增多，FCM分析提示S+G2期占全部细胞比例增多；而在shRNA导致CREG表达下调后，与对照组相比，发现细胞计数减少，BrdU阳性细胞百分比减少，FCM分析可见S+G2期占全部细胞比例减少。（2）Wstern blot提示：与对照组相比，CREG可使ERK、PI3K/Akt信号通路激活，Cyclin E表达增多，RT-PCR发现CREG可在转录水平影响Cyclin E的表达。（3）信号通路阻断剂添加后，BrdU掺入实验及FCM检测提示：尽管PI3K/Akt、ERK信号通路都可影响CREG调控的HUVEC增殖，但ERK通路特异性的介导了CREG对HUVEC增殖的调控，Western blot检测也证实了ERK特异性的介导了CREG对Cyclin E的调控。（4）体外及在体matrigel血管生成实验发现CREG过表达可使毛细血管密度明显增多；小鼠下肢缺血模型制作成功后，以腺病毒感染缺血区肌肉组织，经检测发现过表达CREG的腺病毒感染组与PBS组以及GFP腺病毒相比，术肢体温升高、自体截肢率降低、病理切片提示肌纤维萎缩程度明显减轻，血流灌注成像仪检测结果提示与对照组相比，CREG过表达组术肢/健肢灌注比升高。
结论：
（1）CREG可促进体外培养HUVEC的增殖；（2）ERK/Cyclin E通路介导了CREG对HUVEC增殖的调控作用；（3）CREG过表达能促进小鼠缺血下肢的血管新生。本研究为PAD的治疗提供了一个新的靶点，也为CREG在缺血性心肌病、经皮冠脉内介入治疗术后支架内再狭窄及迟发性血栓的防治中的应用提供了新的证据。
Object：
Endothelial injury is one of the initiating causes of atherosclerosis, myocardialinfarction, intrastent restenosis after percutaneous coronary intervention, peripheral arterialdisease (PAD) and shock. Promoting integrity of the endothelial cells (EC) and maintainingtheir normal function will provide a new way to the prevention and treatment for the abovediseases. The aim of this study is to investigate the function and underlying mechanism ofcellular repressor of E1A-stimulated genes (CREG), a newly found transcription regulatinggene, on cell cycle of human umbilical vein endothelial cell (HUVEC). We further explorethe role of CREG in regulating angiogenesis in a mice lower limb ischemia model.
Method：
(1) HUVEC were infected with adenovirus carrying either green fluorescence protein(GFP) or CREG to establish GFP control group and CREG over-expression group. Cellcounting analysis, BrdU incorporation assay, and flow cytometry (FCM) were performed toassess role of CREG in regulating HUVEC proliferation. Then Western Blot was used todetect expression of CREG, signaling molecules, cyclins and cyclin-dependent kinases(CDKs). Reverse transcription-polymerase chain reaction (RT-PCR) was applied to detectdifference in transcriptional expression of cyclins.(2) Stable HUVEC clones with CREGsilenced down or expressing scrambled negative control short hairpin RNA (shRNA)sequence were established by puromycin selection after retroviral infection. Cell countinganalysis, BrdU incorporation assay, and FCM were performed to evaluate the function ofCREG on HUVEC proliferation from perspective of loss of function.(3) According to theresults of Western blot, the signaling pathways affected by CREG significantly wereblocked with corresponding blockers. HUVEC proliferation was assessed by cell counting analysis, BrdU incorporation assay and FCM to determine the signaling pathway throughwhich CREG exerted its function. To identify the CREG related signaling pathways andCyclins, the expressions of Cyclins and signaling pathway protein were detected byWestern blot.(4) After blocking VEGF signaling pathway with anti-VEGF165neutralizingantibody in HUVEC with CREG over-expression or adding human recombinant VEGF165(rhVEGF165) in HUVEC with CREG knock down, cell proliferation was detected by cellcounting analysis, BrdU incorporation assay, FCM analysis, and the expressions of Cyclinsand signaling pathway protein was detected by Western blot at the same time to determinewhether VEGF is involved in regulation of CREG on HUVEC proliferation and Cyclins.(5)Using the normal HUVEC and GFP adenovirus infected HUVEC as control; the effect ofCREG over expression on angiogenesis was detected by the matrigel angiogenesis assay invitro and in vivo in mice. After establishment of mice lower limb ischemia model, withPBS and GFP-carrying adenovirus as control, the adenovirus carrying CREG was used toinfected local ischemia muscle tissue. To evaluate CREG function on the treatment of micelower limb ischemia and the effect on angiogenesis, the autologous amputation rate and theratio of trouble limb temperature that of normal limb were recorded, the pathologicalchange of skeletal muscle fiber was detected by H&E staining, and the blood perfusionratio of trouble limb to the contralateral was measured by blood flow perfusion imagingdetection.
Results：
(1) Compared with control groups, HUVEC with CREG over-expression showedhigher cell numbers by cell counting, increased BrdU positive cells percentage by BrdUincorporation experiment and increased percentage of S+G2phase by FCM analysis. Incontrast, HUVEC with CREG silenced down showed lower cell numbers by cell counting,decreased BrdU positive cells percentage by BrdU incorporation experiment and declinedpercentage of S+G2phase by FCM analysis.(2) Western blot analysis showed that CREGcould up-regulate expression of Cyclin E and activate the ERK, PI3K/Akt signalingpathway compared with control groups. RT-PCR found CREG could regulate theexpression of Cyclin E at transcription level.(3) After addition of signaling pathwayblockers, BrdU incorporation experiment and FCM analysis revealed that the promotioneffect of CREG on HUVEC proliferation was specifically mediated by ERK pathway, but not by PI3K/Akt pathway, although the two signaling pathway can both affect HUVECproliferation. As the same, it’s ERK but not PI3K/Akt signal pathway that mediates theregulation of CREG on CyclinE expression.(4) In vitro and in vivo matrigel angiogenesisexperiments found that CREG over-expression could significantly increase the capillarydensity. In the mice lower limb ischemia models, compared with the PBS and GFPadenovirus control groups, application of CREG adenovirus to infect ischemic muscletissue showed high temperature ratio of trouble limb to healthy limb, lower rate ofautologous amputation, significantly alleviated atrophy of muscle fibers and improvedperfusion ratio of trouble limb to healthy limb.
Conclusion：
(1) CREG can promote the proliferation of HUVEC cultured in vitro;(2) The functionof CREG regulation on HUVEC proliferation was mediated by ERK/Cyclin E pathway;(3)CREG over-expression can promote angiogenesis in mice lower limbs ischemic models.This study provides a new target of CREG for the treatment of PAD, and also a new prooffor CREG in the prevention and treatment of ischemic heart disease, intrastent restenosisafter percutaneous coronary intervention and late-onset thrombosis.
内皮损伤是动脉粥样硬化、心肌梗死、经皮冠状动脉介入治疗术后支架内再狭窄、下肢动脉硬化闭塞症（PAD）、休克等各种血栓性疾病的始动病因。促进内皮细胞（EC）的完整性，维持其正常功能，将为此类疾病提供新的防治手段。本研究探讨了一个新近发现的调控细胞转录的基因——E1A激活基因阻遏子（CREG）调控人脐静脉内皮细胞（HUVEC）周期的作用和机制，并在小鼠下肢缺血模型中初步探讨了其对血管新生的影响。
方法：
（1）以绿色荧光蛋白（GFP）腺病毒感染HUVEC作为对照，应用CREG腺病毒使HUVEC过表达CREG，以细胞计数、BrdU掺入实验、流式细胞术（FCM）检测CREG对HUVEC增殖的影响，Western blot检测HUVEC中CREG、信号通路、细胞周期蛋白（Cyclins）及细胞周期蛋白依赖性激酶（CDKs）的表达，RT-PCR检测Cyclins在转录水平上的表达差异。（2）以表达短发卡RNA （shRNA）序列的阴性空载体为对照，将CREG表达沉默的shRNA载体转染至逆转录病毒，产生病毒后感染HUVEC，经嘌呤霉素筛选，得到CREG表达下调的HUVEC；应用细胞计数、BrdU掺入实验、FCM检测从功能缺失角度验证CREG下调对HUVEC增殖的影响。（3）根据信号通路Western blot结果的提示，应用信号通路阻断剂阻断可被CREG明显影响的信号通路，以BrdU掺入实验及FCM检测细胞增殖并确定CREG发挥生物学作用的通路，Westernblot检测蛋白表达及信号通路蛋白及Cyclins的表达，确定CREG相关的信号通路及Cyclins。（4）在腺病毒感染造成CREG过表达的HUVEC中使用血管内皮生长因子中和抗体（VEGF NA）阻断VEGF的作用；在CREG被干扰造成其表达下调的HUVEC中添加重组人血管内皮生长因子（rhVEGF165），以细胞计数、BrdU掺入试验、FCM检测细胞增殖，同时以Western blot检测信号通路以及Cyclins的表达，确定血管内皮生长因子（VEGF）是否参与了CREG调控HUVEC增殖及Cyclins表达的作用。（5）以正常的以及感染GFP腺病毒的HUVEC作为对照，应用体外及小鼠在体matrigel血管生成实验检测HUVEC感染CERG腺病毒后对血管生成的影响；制作小鼠下肢缺血模型后，以PBS、GFP腺病毒做为对照，应用CREG腺病毒感染局部缺血肌肉组织，观测术肢体温、自体截肢率，以病理切片观测肌纤维形态改变，应用血流灌注成像仪检测术肢/健肢灌注比，检测CREG对小鼠下肢缺血的治疗作用以及对血管新生的影响。
结果：
（1）与对照组相比，HUVEC经腺病毒感染过表达CREG后，细胞计数增多，BrdU掺入实验中BrdU阳性细胞百分比增多，FCM分析提示S+G2期占全部细胞比例增多；而在shRNA导致CREG表达下调后，与对照组相比，发现细胞计数减少，BrdU阳性细胞百分比减少，FCM分析可见S+G2期占全部细胞比例减少。（2）Wstern blot提示：与对照组相比，CREG可使ERK、PI3K/Akt信号通路激活，Cyclin E表达增多，RT-PCR发现CREG可在转录水平影响Cyclin E的表达。（3）信号通路阻断剂添加后，BrdU掺入实验及FCM检测提示：尽管PI3K/Akt、ERK信号通路都可影响CREG调控的HUVEC增殖，但ERK通路特异性的介导了CREG对HUVEC增殖的调控，Western blot检测也证实了ERK特异性的介导了CREG对Cyclin E的调控。（4）体外及在体matrigel血管生成实验发现CREG过表达可使毛细血管密度明显增多；小鼠下肢缺血模型制作成功后，以腺病毒感染缺血区肌肉组织，经检测发现过表达CREG的腺病毒感染组与PBS组以及GFP腺病毒相比，术肢体温升高、自体截肢率降低、病理切片提示肌纤维萎缩程度明显减轻，血流灌注成像仪检测结果提示与对照组相比，CREG过表达组术肢/健肢灌注比升高。
结论：
（1）CREG可促进体外培养HUVEC的增殖；（2）ERK/Cyclin E通路介导了CREG对HUVEC增殖的调控作用；（3）CREG过表达能促进小鼠缺血下肢的血管新生。本研究为PAD的治疗提供了一个新的靶点，也为CREG在缺血性心肌病、经皮冠脉内介入治疗术后支架内再狭窄及迟发性血栓的防治中的应用提供了新的证据。
Object：
Endothelial injury is one of the initiating causes of atherosclerosis, myocardialinfarction, intrastent restenosis after percutaneous coronary intervention, peripheral arterialdisease (PAD) and shock. Promoting integrity of the endothelial cells (EC) and maintainingtheir normal function will provide a new way to the prevention and treatment for the abovediseases. The aim of this study is to investigate the function and underlying mechanism ofcellular repressor of E1A-stimulated genes (CREG), a newly found transcription regulatinggene, on cell cycle of human umbilical vein endothelial cell (HUVEC). We further explorethe role of CREG in regulating angiogenesis in a mice lower limb ischemia model.
Method：
(1) HUVEC were infected with adenovirus carrying either green fluorescence protein(GFP) or CREG to establish GFP control group and CREG over-expression group. Cellcounting analysis, BrdU incorporation assay, and flow cytometry (FCM) were performed toassess role of CREG in regulating HUVEC proliferation. Then Western Blot was used todetect expression of CREG, signaling molecules, cyclins and cyclin-dependent kinases(CDKs). Reverse transcription-polymerase chain reaction (RT-PCR) was applied to detectdifference in transcriptional expression of cyclins.(2) Stable HUVEC clones with CREGsilenced down or expressing scrambled negative control short hairpin RNA (shRNA)sequence were established by puromycin selection after retroviral infection. Cell countinganalysis, BrdU incorporation assay, and FCM were performed to evaluate the function ofCREG on HUVEC proliferation from perspective of loss of function.(3) According to theresults of Western blot, the signaling pathways affected by CREG significantly wereblocked with corresponding blockers. HUVEC proliferation was assessed by cell counting analysis, BrdU incorporation assay and FCM to determine the signaling pathway throughwhich CREG exerted its function. To identify the CREG related signaling pathways andCyclins, the expressions of Cyclins and signaling pathway protein were detected byWestern blot.(4) After blocking VEGF signaling pathway with anti-VEGF165neutralizingantibody in HUVEC with CREG over-expression or adding human recombinant VEGF165(rhVEGF165) in HUVEC with CREG knock down, cell proliferation was detected by cellcounting analysis, BrdU incorporation assay, FCM analysis, and the expressions of Cyclinsand signaling pathway protein was detected by Western blot at the same time to determinewhether VEGF is involved in regulation of CREG on HUVEC proliferation and Cyclins.(5)Using the normal HUVEC and GFP adenovirus infected HUVEC as control; the effect ofCREG over expression on angiogenesis was detected by the matrigel angiogenesis assay invitro and in vivo in mice. After establishment of mice lower limb ischemia model, withPBS and GFP-carrying adenovirus as control, the adenovirus carrying CREG was used toinfected local ischemia muscle tissue. To evaluate CREG function on the treatment of micelower limb ischemia and the effect on angiogenesis, the autologous amputation rate and theratio of trouble limb temperature that of normal limb were recorded, the pathologicalchange of skeletal muscle fiber was detected by H&E staining, and the blood perfusionratio of trouble limb to the contralateral was measured by blood flow perfusion imagingdetection.
Results：
(1) Compared with control groups, HUVEC with CREG over-expression showedhigher cell numbers by cell counting, increased BrdU positive cells percentage by BrdUincorporation experiment and increased percentage of S+G2phase by FCM analysis. Incontrast, HUVEC with CREG silenced down showed lower cell numbers by cell counting,decreased BrdU positive cells percentage by BrdU incorporation experiment and declinedpercentage of S+G2phase by FCM analysis.(2) Western blot analysis showed that CREGcould up-regulate expression of Cyclin E and activate the ERK, PI3K/Akt signalingpathway compared with control groups. RT-PCR found CREG could regulate theexpression of Cyclin E at transcription level.(3) After addition of signaling pathwayblockers, BrdU incorporation experiment and FCM analysis revealed that the promotioneffect of CREG on HUVEC proliferation was specifically mediated by ERK pathway, but not by PI3K/Akt pathway, although the two signaling pathway can both affect HUVECproliferation. As the same, it’s ERK but not PI3K/Akt signal pathway that mediates theregulation of CREG on CyclinE expression.(4) In vitro and in vivo matrigel angiogenesisexperiments found that CREG over-expression could significantly increase the capillarydensity. In the mice lower limb ischemia models, compared with the PBS and GFPadenovirus control groups, application of CREG adenovirus to infect ischemic muscletissue showed high temperature ratio of trouble limb to healthy limb, lower rate ofautologous amputation, significantly alleviated atrophy of muscle fibers and improvedperfusion ratio of trouble limb to healthy limb.
Conclusion：
(1) CREG can promote the proliferation of HUVEC cultured in vitro;(2) The functionof CREG regulation on HUVEC proliferation was mediated by ERK/Cyclin E pathway;(3)CREG over-expression can promote angiogenesis in mice lower limbs ischemic models.This study provides a new target of CREG for the treatment of PAD, and also a new prooffor CREG in the prevention and treatment of ischemic heart disease, intrastent restenosisafter percutaneous coronary intervention and late-onset thrombosis.
引文
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