PAI-1和ET-1在维持性血液透析患者动脉硬化中的作用
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摘要
目的:探讨纤溶成分中I型纤溶酶原激活物抑制因子(plasminogen activator inhibitor-1,PAI-1)、组织型纤溶酶原激活因子(tissue-type plasminogen activator,t-PA)与内皮素-1(endothelin-1,ET-1)在慢性肾衰竭维持性血液透析(maintenance hemodialysis,MHD)患者动脉硬化病变过程中所起的作用。方法:采用免疫组织化学与图像分析方法检测19例慢性肾衰竭MHD患者与11例对照组髂内动脉的血管壁病理改变与钙化程度,检测PAI-1,t-PA和ET-1在血管壁的表达情况;其中病例组按年龄分为40岁以上组(11人)和40岁以下组(8人),对照组均为40岁以下。收集所有研究对象的临床资料,包括年龄、性别、血液透析时间、血压、血尿素氮(blood urea nitrogen,BUN)、血肌酐(serum creatinine,SCr)等。结果:MHD患者与正常对照组比较,髂内动脉血管壁中膜厚度增加,中膜厚度/内径、中膜面积/内腔面积值均增大(P<0.05),钙化程度增加(P<0.05);在MHD患者不同年龄组间比较,40岁以上组比40岁以下组动脉血管壁中膜厚度增加,中膜厚度/内径值、中膜面积/内腔面积值均增大(P<0.05));血管壁中膜厚度与年龄、血压呈正相关(P<0.01);PAI-1,t-PA,ET-1在MHD患者髂内动脉管壁中较正常对照组的表达上调(P<0.05);PAI-1和ET-1在40岁以上组较40岁以下组的表达上调(P<0.05),t-PA在两组中的表达差异无统计学意义;PAI-1或ET-1的表达与年龄或血压呈正相关;t-PA的表达与年龄、血压无相关性(P>0.05)。PAI-1或ET-1的表达与中膜厚度或钙化程度呈正相关(P<0.05或P<0.01)。血液透析时间与血管壁中膜厚度、中膜厚度/内径、中膜面积/内腔面积值、钙化程度、PAI-1、t-PA以及ET-1的表达无相关性。结论:1)MHD患者存在动脉硬化;40岁以上的MHD患者动脉硬化程度较40岁以下者更为严重;且随着血压的增高,动脉硬化程度加重。2)PAI-1和ET-1的异常表达在MHD患者动脉硬化进程中起重要作用,t-PA在MHD患者动脉硬化进程中作用不明显。3)PAI-1或ET-1的表达与中膜厚度或钙化程度呈正相关,提示二者可能有助于临床上对MHD患者动脉硬化程度的判断。4)血液透析治疗时间可能不是加速动脉硬化的潜在因素。
Objective: To investigate the effect of plasminogen activator inhibitor-1(PAI-1),tissue type plasminogen activator(t-PA),and endothelin-1(ET-1) on the atherosclerosis progress in the maintenance hemodialysis patients.Methods: We enrolled 19 patients with maintenance hemodialysis(MHD) and 11 healthy people as control.Patients were divided into 2 groups according to their age above or below 40 years old(11 and 8 in each,respectively),whereas the subjects in control group were below 40 years old.All the clinical information of the research subjects was collected: including age,gender,time of hemodialysis,blood pressure,blood urea nitrogen(BUN),and serum creatinine(SCr).Immunohistochemistry and pathological image analysis were used to investigate the pathological changes,calcification and the expression of PAI-1,t-PA,and ET-1 on the blood vessel.Results: Compared with the age-matched healthy control group,there were higher blood vascular media thickness,blood vascular media thickness/diagmeter ratio,blood vascular media thickness area/vascular inter-wall area ratio(P<0.05) and more calcification(P<0.05) in the the internal iliac artery in the chronic renal failure MHD patients.All the results were similar when compared the above 40 years old group with the below 40 years old one in the chronic renal failure MHD patients.There were positive correlation of blood vascular media thickness with age and blood pressure(P<0.05).Expression of PAI-1,ET-1,t-PA on the internal iliac artery vessel was elevated in the chronic renal failure MHD patients compared with the health control(P<0.05).The level of PAI-1 or ET-1 was much higher in the above 40 years old group than the below 40 years old one in the chronic renal failure MHD patients,whereas there was no significant difference in the t-PA expression between the 2 groups(P<0.05).There were positive correlation of PAI-1 or ET-1 expression with age and blood pressure(P<0.05).There were positive correlation of PAI-1 or ET-1 expression with blood vascular media thickness and calcification(P<0.05 or P<0.01).There was no correlation of hemodialysis time with blood vascular media thickness,calcification,PAI-1,t-PA,or ET-1 expressions.Conclusion: MHD patients accompany with atherosclerosis which is severer in the patients above 40 years old than the patients below 40 years old.The higher of the blood pressure,the severer of the atherosclerosis.Abnormal expression of PAI-1 plays an important role in the progress of the atherosclerosis in the chronic renal failure MHD patients,whereas t-PA has no function in this process.The level of PAI-1 and ET-1 would be helpful to evaluating the degree of atherosclerosis in the chronic renal failure MHD patients.Hemodialysis time may not be a potential accelerator for atherosclerosis progression
Objective: To investigate the effect of plasminogen activator inhibitor-1(PAI-1),tissue type plasminogen activator(t-PA),and endothelin-1(ET-1) on the atherosclerosis progress in the maintenance hemodialysis patients.Methods: We enrolled 19 patients with maintenance hemodialysis(MHD) and 11 healthy people as control.Patients were divided into 2 groups according to their age above or below 40 years old(11 and 8 in each,respectively),whereas the subjects in control group were below 40 years old.All the clinical information of the research subjects was collected: including age,gender,time of hemodialysis,blood pressure,blood urea nitrogen(BUN),and serum creatinine(SCr).Immunohistochemistry and pathological image analysis were used to investigate the pathological changes,calcification and the expression of PAI-1,t-PA,and ET-1 on the blood vessel.Results: Compared with the age-matched healthy control group,there were higher blood vascular media thickness,blood vascular media thickness/diagmeter ratio,blood vascular media thickness area/vascular inter-wall area ratio(P<0.05) and more calcification(P<0.05) in the the internal iliac artery in the chronic renal failure MHD patients.All the results were similar when compared the above 40 years old group with the below 40 years old one in the chronic renal failure MHD patients.There were positive correlation of blood vascular media thickness with age and blood pressure(P<0.05).Expression of PAI-1,ET-1,t-PA on the internal iliac artery vessel was elevated in the chronic renal failure MHD patients compared with the health control(P<0.05).The level of PAI-1 or ET-1 was much higher in the above 40 years old group than the below 40 years old one in the chronic renal failure MHD patients,whereas there was no significant difference in the t-PA expression between the 2 groups(P<0.05).There were positive correlation of PAI-1 or ET-1 expression with age and blood pressure(P<0.05).There were positive correlation of PAI-1 or ET-1 expression with blood vascular media thickness and calcification(P<0.05 or P<0.01).There was no correlation of hemodialysis time with blood vascular media thickness,calcification,PAI-1,t-PA,or ET-1 expressions.Conclusion: MHD patients accompany with atherosclerosis which is severer in the patients above 40 years old than the patients below 40 years old.The higher of the blood pressure,the severer of the atherosclerosis.Abnormal expression of PAI-1 plays an important role in the progress of the atherosclerosis in the chronic renal failure MHD patients,whereas t-PA has no function in this process.The level of PAI-1 and ET-1 would be helpful to evaluating the degree of atherosclerosis in the chronic renal failure MHD patients.Hemodialysis time may not be a potential accelerator for atherosclerosis progression
引文
1.Sarnak MJ,Levey AS.Cardiovascular disease and chronic renal disease:a new paradigm[J].Am J Kidney Dis,2000,35(4 Suppl 1):117-131.
2.Wayhs R,Zelinger A,Raggi P.High coronary artery calcium scorespose an extremely elevated risk for heart events[J].J Am Coll Cardiol,2002,39(2):225-230.
3.Goodman WG,Goldin J,Kuizon BD,et al.Coroary-artery calcificationin young adults with end-stage renal disease who are undergoingdialysis[J].N Engl J Med,2000,342(20):1478-1483.
4.Foley RN,Parfrey PS,Sarnak MJ.Clinical epidemiolog y ofcardiovascular disease in chronic renal disease[J].Am J Kidney Dis,1998,32(5):112-119.
5.Furmotor T,Fujii S,Saito N,et al.Relationships between branch arteryflow mediated dilation and carotid artery intimamedia thick in patientswith artery disease[J].Jpn Heart J,2002,43(2):121-125.
6.Ekmek i H,Güng r ztürk Z,Ekmek i OB,et al.Significanceof vitronectin and PAI-1 activity levels in carotid artery disease:comparison of symptomatic and asymptomatic patients[J].MinervaMed,2013,104(2):215-224.
7.Sakata T,Mannami T,Baba S,et al.Potential of free-form TFPI andPAI-1 to be useful markers of early atherosclerosis in a Japanese generalpopulation(the Suita Study):association with the intimal-medialthickness of carotid arteries[J].Atherosclerosis,2004,176(2):355-360.
8.Inoue A,Yanagisawa M,Kimura S,et al.The human endothelin family:three structurally and pharmacologically distinct isopeptides predictedby three separate genes[J].Proc Natl Acad Sci USA,1989,86(8):2863-2867.
9.Ohkita M,Tawa M,Kitada K,et al.Pathophysiological roles ofendothelin receptors in cardiovascular diseases[J].J Pharmacol Sci,2012,119(4):302-313.
10.Pernow J,Shemyakin A,B hm F.New perspectives on endothelin-1in atherosclerosis and diabetes mellitus[J].Life Sci,2012,91(13/14):507-516.
11.Ploplis VA,Cornelissen I,Sandoval-Cooper MJ,et al.Remodeling ofthe vessel wall after copper-induced injury is highly attenuated in micewith a total deficiency of plasminogen activator inhibitor-1[J].Am JPathol,2001,158(1):107-117.
12.Cetinkaya Demir B,Uyar Y,Ozbilgin K,et al.Effect of raloxifene andatorvastatin in atherosclerotic process in ovariectomized rats[J].JObstet Gynaecol Res,2013,39(1):229-236.
13.Rautureau Y,Schiffrin EL.Endothelin in hypertension:an update[J].Curr Opin Nephrol Hypertens,2012,21(2):128-136.
14.Yang P,Li Y,Li JJ,et al.Up-regulating PPAR-γexpression and NOconcentration,and down-regulating PAI-1 concentration in a rabbitatherosclerotic model:the possible antiatherogenic and antithromboticeffects of atorvastatin[J].Int J Cardiol,2010,139(3):213-217.
15.申洪.免疫组织化学染色定量方法研究(III)[J].中国组织化学与细胞化学杂志,1995,4(1):89-91.SHEN Hong.Study of the quartitative method of immuno-histochemistry(III)[J].Chinese Journal of Histochemistry andCytochemistry,1995,4(1):89-91.
16.Takashi S,Takashi K,Kenichi S,et al.Phosphate overload acceleratesvascular calcium deposition in end-stage renal disease patients[J].Nephrol Dial Transplant,2003,18(Suppl 13):86-89.
17.Jono S,Mckee MD,Murry CE,et al.Phosphate regulation of vascularsmooth muscle cell calcification[J].Circ Res,2000,87(7):E10-E17.
18.Hojs R.Carotid intima-media thickness and plaques in hemodialysispatients[J].Artif Organs,2000,24(9):691-695.
19.Smith EB.Fibrinogen,fibrin and the arterial wall[J].Eur Heart J,1995,16(Suppl A):11-15.
20.Nachman RI.Thrombosis and atherogenesis:molecula rconnections[J].Blood,1992,79(8):1897-1906.
21.Naya M,Tsukamoto T,Inubushi M,et al.Elevated plasma plasminogenactivator inhibitor type-1 is an independent predictor of coronarymicrovascular dysfunction in hypertension[J].Cric J,2007,71(3):348-353.
22.孙东风,诸骏人,宋后燕.动脉粥样硬化病变组织中PAI-1和uPA抗原表达的变化[J].中华老年医学杂志,1997,16(6):351-353.SUN Dongfeng,ZHU Junren,SONG Houyan.Expression of PAI-1 anduPA antigens in the human atherosclerotic arteries[J].Chinese Journalof Geriatrics,1997,16(6):351-353.
23.Bicakcigil M,Tasan D,Tasdelen N,et al.Role of fibrinolytic parametersand plasminogen activator inhibitor 1(PAI-1)promoter polymorphismon premature atherosclrosis in sle patients[J].Lupus,2011,20(10):1063-1071.
24.Lerman A,Webster MW,Chesebro JH,et al.Circulating and tissueendothelin immunoreactivity in hypercholesterolemic pigs[J].Circulation,1993,88(6):2923-2928.
25.Boulanger CM,TannerFC,Bea ML,et al.Oxidized low densitylipoproteins induce mRNA expression and release of endothelin fromhuman and porcine endothelium[J].Circ Res,1992,70(6):1191.
26.Hirata Y,Takaqi Y,Fukuda Y,et al.Endothelin is a potent mitogen forrat vascular smooth muscle cells[J].Atherosclerosis,1989,78(2/3):225-228.
27.Bobik A,Grooms A,Millar JA,et al.Growth factor activity ofendothelin on vascular smooth muscle[J].Am J Physiol,1990,258(3Pt 1):C408-415.
28.Weissberg PL,Witchell C,Davenport AP,et al.The endothelinpeptides ET-1,ET-2,ET-3 and sarafotoxin S6b are co-mitogenic withplatelet-derived growth factor for vascular smooth muscle cells[J].Atherosclerosis,1990,85(2/3):257-262.
29.Ross R.The pathogenesis of atherosclerosis:a perspective for the1990s[J].Nature,1993,362(6423):801-809.
30.Achmad TH,Rao GS.Chemotaxis of human blood monocytestoward endothelin-1 and the influence of calcium channel blockers[J].Biochem Biophys Res Commun,1992,189(2):994-1000.
31.Parthasarathy S,Steinberg D,Witztum JL.The role of oxidized low-density lipoproteins in the pathogenesis of atherosclerosis[J].Ann RevMed,1992,43:219-225.
32.Av iram M.Modif ied forms of low densit y lipoprotein andatherosclerosis[J].Atherosclerosis,1993,98(1):1-9.
33.Ishida K,Takeshige K,Minakami S.Endothelin-1 enhances superoxidegeneration of human neutrophils stimulated by the chemotactic peptideN-formyl-methionyl-leucyl-phenylalanine[J].Biochem Biophys ResCommun,1990,173(2):496-500.
34.Arikan H,Koc M,Tuglular S,et al.Elevated plasma levels of PAI-1predict cardiovascular events and cardiovascular mortality in prevalentperitoneal dialysis patients[J].Ren Fail,2009,31(6):438-445.
35.Shoji T,Emoto M,Tabata T,et al.Advanced atherosclerosis inpredialysis patients with chronic renal failure[J].Kidney Intern,2002,61(6):2187-2182.
36.Pascasio L,Blanco F,Giorgini A,et al.Echo color Doppler imagingof carotid vessels in hemodialysis patients:evidence of high levels ofatherosclerotic lesions[J].Am J Kidney Dis,1996,28(5):713-720.
37.Damjanovic T,Dimkovic N.Dialysis as a risk factor for development ofatherosclerosis[J].Med Pregl,2003,56(1/2):17-21.
2.Wayhs R,Zelinger A,Raggi P.High coronary artery calcium scorespose an extremely elevated risk for heart events[J].J Am Coll Cardiol,2002,39(2):225-230.
3.Goodman WG,Goldin J,Kuizon BD,et al.Coroary-artery calcificationin young adults with end-stage renal disease who are undergoingdialysis[J].N Engl J Med,2000,342(20):1478-1483.
4.Foley RN,Parfrey PS,Sarnak MJ.Clinical epidemiolog y ofcardiovascular disease in chronic renal disease[J].Am J Kidney Dis,1998,32(5):112-119.
5.Furmotor T,Fujii S,Saito N,et al.Relationships between branch arteryflow mediated dilation and carotid artery intimamedia thick in patientswith artery disease[J].Jpn Heart J,2002,43(2):121-125.
6.Ekmek i H,Güng r ztürk Z,Ekmek i OB,et al.Significanceof vitronectin and PAI-1 activity levels in carotid artery disease:comparison of symptomatic and asymptomatic patients[J].MinervaMed,2013,104(2):215-224.
7.Sakata T,Mannami T,Baba S,et al.Potential of free-form TFPI andPAI-1 to be useful markers of early atherosclerosis in a Japanese generalpopulation(the Suita Study):association with the intimal-medialthickness of carotid arteries[J].Atherosclerosis,2004,176(2):355-360.
8.Inoue A,Yanagisawa M,Kimura S,et al.The human endothelin family:three structurally and pharmacologically distinct isopeptides predictedby three separate genes[J].Proc Natl Acad Sci USA,1989,86(8):2863-2867.
9.Ohkita M,Tawa M,Kitada K,et al.Pathophysiological roles ofendothelin receptors in cardiovascular diseases[J].J Pharmacol Sci,2012,119(4):302-313.
10.Pernow J,Shemyakin A,B hm F.New perspectives on endothelin-1in atherosclerosis and diabetes mellitus[J].Life Sci,2012,91(13/14):507-516.
11.Ploplis VA,Cornelissen I,Sandoval-Cooper MJ,et al.Remodeling ofthe vessel wall after copper-induced injury is highly attenuated in micewith a total deficiency of plasminogen activator inhibitor-1[J].Am JPathol,2001,158(1):107-117.
12.Cetinkaya Demir B,Uyar Y,Ozbilgin K,et al.Effect of raloxifene andatorvastatin in atherosclerotic process in ovariectomized rats[J].JObstet Gynaecol Res,2013,39(1):229-236.
13.Rautureau Y,Schiffrin EL.Endothelin in hypertension:an update[J].Curr Opin Nephrol Hypertens,2012,21(2):128-136.
14.Yang P,Li Y,Li JJ,et al.Up-regulating PPAR-γexpression and NOconcentration,and down-regulating PAI-1 concentration in a rabbitatherosclerotic model:the possible antiatherogenic and antithromboticeffects of atorvastatin[J].Int J Cardiol,2010,139(3):213-217.
15.申洪.免疫组织化学染色定量方法研究(III)[J].中国组织化学与细胞化学杂志,1995,4(1):89-91.SHEN Hong.Study of the quartitative method of immuno-histochemistry(III)[J].Chinese Journal of Histochemistry andCytochemistry,1995,4(1):89-91.
16.Takashi S,Takashi K,Kenichi S,et al.Phosphate overload acceleratesvascular calcium deposition in end-stage renal disease patients[J].Nephrol Dial Transplant,2003,18(Suppl 13):86-89.
17.Jono S,Mckee MD,Murry CE,et al.Phosphate regulation of vascularsmooth muscle cell calcification[J].Circ Res,2000,87(7):E10-E17.
18.Hojs R.Carotid intima-media thickness and plaques in hemodialysispatients[J].Artif Organs,2000,24(9):691-695.
19.Smith EB.Fibrinogen,fibrin and the arterial wall[J].Eur Heart J,1995,16(Suppl A):11-15.
20.Nachman RI.Thrombosis and atherogenesis:molecula rconnections[J].Blood,1992,79(8):1897-1906.
21.Naya M,Tsukamoto T,Inubushi M,et al.Elevated plasma plasminogenactivator inhibitor type-1 is an independent predictor of coronarymicrovascular dysfunction in hypertension[J].Cric J,2007,71(3):348-353.
22.孙东风,诸骏人,宋后燕.动脉粥样硬化病变组织中PAI-1和uPA抗原表达的变化[J].中华老年医学杂志,1997,16(6):351-353.SUN Dongfeng,ZHU Junren,SONG Houyan.Expression of PAI-1 anduPA antigens in the human atherosclerotic arteries[J].Chinese Journalof Geriatrics,1997,16(6):351-353.
23.Bicakcigil M,Tasan D,Tasdelen N,et al.Role of fibrinolytic parametersand plasminogen activator inhibitor 1(PAI-1)promoter polymorphismon premature atherosclrosis in sle patients[J].Lupus,2011,20(10):1063-1071.
24.Lerman A,Webster MW,Chesebro JH,et al.Circulating and tissueendothelin immunoreactivity in hypercholesterolemic pigs[J].Circulation,1993,88(6):2923-2928.
25.Boulanger CM,TannerFC,Bea ML,et al.Oxidized low densitylipoproteins induce mRNA expression and release of endothelin fromhuman and porcine endothelium[J].Circ Res,1992,70(6):1191.
26.Hirata Y,Takaqi Y,Fukuda Y,et al.Endothelin is a potent mitogen forrat vascular smooth muscle cells[J].Atherosclerosis,1989,78(2/3):225-228.
27.Bobik A,Grooms A,Millar JA,et al.Growth factor activity ofendothelin on vascular smooth muscle[J].Am J Physiol,1990,258(3Pt 1):C408-415.
28.Weissberg PL,Witchell C,Davenport AP,et al.The endothelinpeptides ET-1,ET-2,ET-3 and sarafotoxin S6b are co-mitogenic withplatelet-derived growth factor for vascular smooth muscle cells[J].Atherosclerosis,1990,85(2/3):257-262.
29.Ross R.The pathogenesis of atherosclerosis:a perspective for the1990s[J].Nature,1993,362(6423):801-809.
30.Achmad TH,Rao GS.Chemotaxis of human blood monocytestoward endothelin-1 and the influence of calcium channel blockers[J].Biochem Biophys Res Commun,1992,189(2):994-1000.
31.Parthasarathy S,Steinberg D,Witztum JL.The role of oxidized low-density lipoproteins in the pathogenesis of atherosclerosis[J].Ann RevMed,1992,43:219-225.
32.Av iram M.Modif ied forms of low densit y lipoprotein andatherosclerosis[J].Atherosclerosis,1993,98(1):1-9.
33.Ishida K,Takeshige K,Minakami S.Endothelin-1 enhances superoxidegeneration of human neutrophils stimulated by the chemotactic peptideN-formyl-methionyl-leucyl-phenylalanine[J].Biochem Biophys ResCommun,1990,173(2):496-500.
34.Arikan H,Koc M,Tuglular S,et al.Elevated plasma levels of PAI-1predict cardiovascular events and cardiovascular mortality in prevalentperitoneal dialysis patients[J].Ren Fail,2009,31(6):438-445.
35.Shoji T,Emoto M,Tabata T,et al.Advanced atherosclerosis inpredialysis patients with chronic renal failure[J].Kidney Intern,2002,61(6):2187-2182.
36.Pascasio L,Blanco F,Giorgini A,et al.Echo color Doppler imagingof carotid vessels in hemodialysis patients:evidence of high levels ofatherosclerotic lesions[J].Am J Kidney Dis,1996,28(5):713-720.
37.Damjanovic T,Dimkovic N.Dialysis as a risk factor for development ofatherosclerosis[J].Med Pregl,2003,56(1/2):17-21.