血管生成素样蛋白4(ANGPTL4)在增生型糖尿病视网膜病变患者血清和玻璃体中的表达
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摘要
目的定量检测增生型糖尿病视网膜病变(proliferative diabetic retinopathy,PDR)患者血清和玻璃体内血管生成素样蛋白4(ANGPTL4)的表达,并探索ANGPTL4在PDR中的作用。方法收集需经睫状体平坦部20G标准三通道玻璃体切割术的患者共69例69眼,其中,PDR组49例49眼,对照组(非糖尿病性全层黄斑裂孔或黄斑裂孔性视网膜脱离患者)20例20眼。酶联免疫吸附试验定量检测两组患者血清及玻璃体标本中ANGPTL4表达水平。使用SPSS 17.0统计学软件对数据进行统计学分析。结果 PDR组患者血清中ANGPTL4的表达水平(30.761±2.996)ng·mL~(-1)较对照组患者(35.912±1.763)ng·mL~(-1)低,差异有统计学意义(t=-8.851,P=0.000);玻璃体ANGPTL4的表达水平(14.723±1.324)ng·mL~(-1)较对照组患者(7.892±0.812)ng·mL~(-1)高,差异有统计学意义(t=24.642,P=0.000)。两组患者血清中ANGPTL4表达水平均高于其玻璃体,且PDR组患者血清与玻璃体中ANGPTL4变化呈正相关关系(r=0.884,P=0.000);对照组患者血清与玻璃体中ANGPTL4变化亦呈正相关关系(r=0.881,P=0.000)。PDR组患者血清及玻璃体中ANGPTL4表达水平均与甘油三酯呈正相关,与高密度脂蛋白呈负相关关系(均为P<0.05),而与其他临床指标无明显相关关系。术前玻璃体内注射雷珠单抗与不注射PDR患者血清及玻璃体中ANGPTL4表达水平,差异均无统计学意义(均为P<0.05)。结论 PDR患者血清中ANGPTL4表达水平低于非糖尿病患者,其可能在糖尿病患者糖脂代谢的病理生理过程中发挥了一定的作用;PDR患者玻璃体中ANGPTL4表达水平高于非糖尿病患者,其可能参与了PDR的发生发展过程,针对PDR患者玻璃体中ANGPTL4的高表达进行干预可能为未来PDR患者的治疗提供新的思路。
Objective To detect the level of angiopoietin-like 4(ANGPTL4) in serum and vitreous of patients with proliferative diabetic retinopathy(PDR) quantitatively,and explore the role of ANGPTL4 in PDR.Methods Sixty-nine patients(69 eyes) underwent 20 G standard vitrectomy via pars plana of ciliary were chosen as observation subjects.Among them,the PDR group was contained by 49 cases 49 eyes,the control group was contained by 20 cases 20 eyes which were all without diabetes,including full thickness macular hole and macular hole retinal detachment.Enzyme-linked immunosorbent assay was used to test the concentration of ANGPTL4 in serum and vitreous.All the obtained data was analyzed by SPSS17.0 statistics software.Results The PDR group patients' serum concentration of ANGPTL4(30.761 ±2.996) ng · mL~(-1)was lower than the control group(35.912±1.763) ng·mL significantly(t=-8.851,P=0.000);The concentration of ANGPTL4 in vitreous(14.723 ±1.324) ng · mL~(-1) was significantly higher than that in the control group(7.892 ± 0.812) ng · mL~(-1)(t =24.642,P = 0.000).In the two groups,the concentration of AN GPTL4 in serum was higher than that in vitreous significantly(P < 0.05),and it showed positive correlation between them(r = 0.884,0.881;all P = 0.000).It showed positive correlation between the concentration of ANGPTL4 in serum and triglyceride in the PDR group negative correlation between ANGPTL4 in serum and highdensity lipoprotein cholesterol(all P < 0.05).The concentration of ANGPTL4 in serum of patients with adiposity was higher than that without adiposity(all P < 0.05).Conclusion The level of ANGPTL4 in serum of PDR is lower than those without diabetes ANGPTL4 may participate in the patho physio logy of obesity and metabolic syndrome;The concentration of ANGPTL4 in vitreous of PDR patient is significantly higher than that without diabetes,and may play a role in the angiogenesis of PDR.Therefore,it may provide a new method for treatment of PDR.
Objective To detect the level of angiopoietin-like 4(ANGPTL4) in serum and vitreous of patients with proliferative diabetic retinopathy(PDR) quantitatively,and explore the role of ANGPTL4 in PDR.Methods Sixty-nine patients(69 eyes) underwent 20 G standard vitrectomy via pars plana of ciliary were chosen as observation subjects.Among them,the PDR group was contained by 49 cases 49 eyes,the control group was contained by 20 cases 20 eyes which were all without diabetes,including full thickness macular hole and macular hole retinal detachment.Enzyme-linked immunosorbent assay was used to test the concentration of ANGPTL4 in serum and vitreous.All the obtained data was analyzed by SPSS17.0 statistics software.Results The PDR group patients' serum concentration of ANGPTL4(30.761 ±2.996) ng · mL~(-1)was lower than the control group(35.912±1.763) ng·mL significantly(t=-8.851,P=0.000);The concentration of ANGPTL4 in vitreous(14.723 ±1.324) ng · mL~(-1) was significantly higher than that in the control group(7.892 ± 0.812) ng · mL~(-1)(t =24.642,P = 0.000).In the two groups,the concentration of AN GPTL4 in serum was higher than that in vitreous significantly(P < 0.05),and it showed positive correlation between them(r = 0.884,0.881;all P = 0.000).It showed positive correlation between the concentration of ANGPTL4 in serum and triglyceride in the PDR group negative correlation between ANGPTL4 in serum and highdensity lipoprotein cholesterol(all P < 0.05).The concentration of ANGPTL4 in serum of patients with adiposity was higher than that without adiposity(all P < 0.05).Conclusion The level of ANGPTL4 in serum of PDR is lower than those without diabetes ANGPTL4 may participate in the patho physio logy of obesity and metabolic syndrome;The concentration of ANGPTL4 in vitreous of PDR patient is significantly higher than that without diabetes,and may play a role in the angiogenesis of PDR.Therefore,it may provide a new method for treatment of PDR.
引文
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[5]VAN RAALTE DH,BRANDS M,SERLIE MJ,MUDDE K,STIENSTRA R,SAUERWEIN HP,et al.Angiopoietin-like protein 4 is differentially regulated by glucocorticoids and insulin in vitro and in vivo in healthy humans[J].Exp Clin Endocrinol Diabetes 2012,120(10):598-603.
[6]刘云涛,简磊,潘敬芳.早期糖尿病慢性肾脏疾病患者血清血管生成素样蛋白4水平及吡格列酮影响的观察[J].中国糖尿病杂志,2015,23(4):135-139.LIU YT,JIAN L PAN JF.The serum ANGPTL4 level in patients with early chronic kidney disease in diabetes and the influence of pioglitazone on the level[J].Chin J Diabetes,2015,23(4):135-139.
[7]CILENSEK I,MANKOC S,GLOBOCNIK PETROVIC M,PETROVIC D.The4 a/4 agenotype of the VNTR polymorphism for endothelial nitric oxide synthase(eNOS)gene predicts risk for proliferative diabetic retinopathy in Slovenian patients(Caucasians)with type 2 diabetes mellitus[J].Mol Biol Rep,2012,39(6):7061-7067.
[8]SANG DN,D'AM ORE PA.Is blockade of vascular endothelial growth factor beneficial for all types of diabetic retinopathy[J]?Diabetologia,2008,51(9):1570-1573.
[9]YOKOUCHI H,ETO K,NISHIMURA W,TAKEDA N,KABURAGIY,YAMAMOTO S,et al.Angiopoietin-like protein 4(AN GPTL4)is induced by high glucose in retinal pigment epithelial cells and exhibits potent angiogenic activity on retinal endothelial cells[J].Acta Ophthalmol,2013,91(4):e289-e297.
[10]HUANG RL,TEO Z,CHONG HC,ZHU P,TAN CK,LAM CR,et al.ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters[J].Blood,2011,118(14):3990-4002.
[11]XIN X,RODRIGUES M,UMAPATHI M,KASHIWABUCHI F,MA T,BABAPOOR-FARROKHRAN S,et al.Hypoxic retinal Muller cells promote vascular permeability by HIF-1-dependent up-regulation of angiopoietin-like 4[J].Proc Natl Acad Sci USA,2013,110(36):E3425-E3434.
[12]BANDELLO F,CORVI F,LA SPINA C,BENATTI L,QUERQUES L,CAPUANO V,et al.Outcomes of intravitreal antiVEGF therapy in eyes with both neovascular age-related macular degeneration and diabetic retinopathy[J].Br J Ophthalmol,2016,100(12):1611-1616.
[13]BABAPOOR-FARROKHRAN S,JEE K,PUCHNER B,HASSAN SJ,XIN X,RODRIGUES M,et al.Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy[J].Proc Natl Acad Sci USA,2015,112(23):E3030-E3039.
[14]LU Q,ZOU W,CHEN B,ZOU C,ZHAO M,ZHENG Z.ANGPTL-4 correlates with vascular endothelial growth factor in patients with proliferative diabetic retinopathy[J].Graefes Arch Clin Exp Ophthalmol,2016,254(7):1281-1288.
[15]MEHTA N,QAMAR A,QU L,QASIM AN,MEHTA NN,REILLY MP,et al.Differential association of plasma angiopoietinlike proteins 3 and 4 with lipid and metabolic traits[J].Arteriosder Thromb Vasc Biol,2014,34(5):1057-1063.
[2]LE JAN S,AMY C,CAZES A,MONNOT C,LAMANDE N,FAVIER J,et al.Angiopoietin-like 4 is a proangiogenic factor produced during ischemia and in conventional renal cell carcinoma[J].Am J Pathol,2003,162(5):1521-1528.
[3]SANTULLI G.Angiopoietin-like proteins:a comprehensive look[J].Front Endocrinol,2014,5:4.
[4]XU A,LAM MC,CHAN KW,WANG Y,ZHANG J,HOO RL,et al.Angiopoietin-like protein 4 decreases blood glucose and improves glucose tolerance but induces hyperlipidemia and hepatic steatosis in mice[J].Proc Natl A cad Sci USA,2005,102(17):6086-6091.
[5]VAN RAALTE DH,BRANDS M,SERLIE MJ,MUDDE K,STIENSTRA R,SAUERWEIN HP,et al.Angiopoietin-like protein 4 is differentially regulated by glucocorticoids and insulin in vitro and in vivo in healthy humans[J].Exp Clin Endocrinol Diabetes 2012,120(10):598-603.
[6]刘云涛,简磊,潘敬芳.早期糖尿病慢性肾脏疾病患者血清血管生成素样蛋白4水平及吡格列酮影响的观察[J].中国糖尿病杂志,2015,23(4):135-139.LIU YT,JIAN L PAN JF.The serum ANGPTL4 level in patients with early chronic kidney disease in diabetes and the influence of pioglitazone on the level[J].Chin J Diabetes,2015,23(4):135-139.
[7]CILENSEK I,MANKOC S,GLOBOCNIK PETROVIC M,PETROVIC D.The4 a/4 agenotype of the VNTR polymorphism for endothelial nitric oxide synthase(eNOS)gene predicts risk for proliferative diabetic retinopathy in Slovenian patients(Caucasians)with type 2 diabetes mellitus[J].Mol Biol Rep,2012,39(6):7061-7067.
[8]SANG DN,D'AM ORE PA.Is blockade of vascular endothelial growth factor beneficial for all types of diabetic retinopathy[J]?Diabetologia,2008,51(9):1570-1573.
[9]YOKOUCHI H,ETO K,NISHIMURA W,TAKEDA N,KABURAGIY,YAMAMOTO S,et al.Angiopoietin-like protein 4(AN GPTL4)is induced by high glucose in retinal pigment epithelial cells and exhibits potent angiogenic activity on retinal endothelial cells[J].Acta Ophthalmol,2013,91(4):e289-e297.
[10]HUANG RL,TEO Z,CHONG HC,ZHU P,TAN CK,LAM CR,et al.ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters[J].Blood,2011,118(14):3990-4002.
[11]XIN X,RODRIGUES M,UMAPATHI M,KASHIWABUCHI F,MA T,BABAPOOR-FARROKHRAN S,et al.Hypoxic retinal Muller cells promote vascular permeability by HIF-1-dependent up-regulation of angiopoietin-like 4[J].Proc Natl Acad Sci USA,2013,110(36):E3425-E3434.
[12]BANDELLO F,CORVI F,LA SPINA C,BENATTI L,QUERQUES L,CAPUANO V,et al.Outcomes of intravitreal antiVEGF therapy in eyes with both neovascular age-related macular degeneration and diabetic retinopathy[J].Br J Ophthalmol,2016,100(12):1611-1616.
[13]BABAPOOR-FARROKHRAN S,JEE K,PUCHNER B,HASSAN SJ,XIN X,RODRIGUES M,et al.Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy[J].Proc Natl Acad Sci USA,2015,112(23):E3030-E3039.
[14]LU Q,ZOU W,CHEN B,ZOU C,ZHAO M,ZHENG Z.ANGPTL-4 correlates with vascular endothelial growth factor in patients with proliferative diabetic retinopathy[J].Graefes Arch Clin Exp Ophthalmol,2016,254(7):1281-1288.
[15]MEHTA N,QAMAR A,QU L,QASIM AN,MEHTA NN,REILLY MP,et al.Differential association of plasma angiopoietinlike proteins 3 and 4 with lipid and metabolic traits[J].Arteriosder Thromb Vasc Biol,2014,34(5):1057-1063.