乙酰肝素酶及新生血管在人颈动脉粥样硬化斑块中的表达
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摘要
目的探讨乙酰肝素酶(Hpa)及新生血管在人颈动脉粥样硬化斑块中的表达特点。方法回顾性连续纳入2014年12月至2017年12月首都医科大学附属复兴医院神经外科接受颈动脉内膜切除术治疗的颈内动脉系统粥样硬化性狭窄患者55例(动脉粥样硬化组),经血管超声、CT血管成像和(或) DSA等影像学方法证实。根据美国心脏学会动脉粥样硬化组织病理学分型方法,筛选出结构清楚的晚期动脉粥样硬化斑块(Ⅳ～Ⅵ型)作为颈动脉粥样硬化斑块标本(共73个)。根据形态学分型标准,将73个颈动脉粥样硬化斑块标本分为易损斑块(42个)和移形斑块(31个)。选择同期于北京大学医学部病理学系行尸体解剖,并明确无动脉粥样硬化病变者15例为无动脉粥样硬化组(正常动脉段标本15个)。采用免疫组织化学、免疫荧光染色检测方法,分析颈动脉粥样硬化斑块内Hpa及新生血管的表达特点。结果 (1)正常颈动脉组织中无Hpa表达;颈动脉粥样硬化斑块内,Hpa阳性表达率为64. 4%(47/73)。(2)与移形斑块相比,易损斑块内Hpa阳性表达率增高[92. 9%(39/42)比25. 8%(8/31),χ~2=34. 968,P <0. 01]。(3)新生血管在颈动脉粥样硬化斑块内呈阳性表达,与移行斑块相比,易损斑块内新生血管阳性表达率更高[95. 2%(40/42)比22. 6%(7/31),χ~2=41. 060,P <0. 01]。(4)颈动脉粥样硬化斑块内,Hpa与新生血管表达主要位于斑块的纤维帽及肩部。结论 Hpa在颈动脉粥样硬化晚期病变进展过程中具有一定的作用,颈动脉粥样硬化斑块内Hpa与新生血管表达具有共区域性。
Objective To investigate the expression characteristics of heparinase( Hpa) and angiogenesis in human carotid atherosclerotic plaques. Methods Fifty-five consecutive patients with atherosclerotic stenosis in internal carotid artery system treated with carotid endarterectomy( atherosclerosis group) at the Department of Neurosurgery,Fuxing Hospital,Capital Medical University from December 2014 to December 2017 were enrolled retrospectively. They were confirmed by imaging methods,such as vascular ultrasound,CT angiography and/or DSA. According to the atherosclerotic histopathological classification method of American Heart Association,the well-defined advanced atherosclerotic plaques( types Ⅳ-Ⅵ)were screened as carotid atherosclerotic plaque specimens( n = 73). According to the morphological classification criteria,73 carotid atherosclerotic plaque specimens were divided into vulnerable plaques( n = 42) and metastatic plaques( n = 31). Autopsy was performed at the Department of Pathology,Peking University Medical School at the same time,and 15 patients without atherosclerotic lesions were identified as non-atherosclerotic group( 15 normal arterial specimens). Immunohistochemistry and immunofluorescence staining were used to analyze the expression characteristics of Hpa and neovascularization in carotid atherosclerotic plaque. Results( 1) There was no Hpa expression in normal arterial tissue; in the carotid atherosclerotic plaque,the positive expression rate of Hpa was 64. 4%( 47/73).( 2) Compared with the metastatic plaques,the positive expression rate of Hpa in the vulnerable plaques increased( 92. 9% [39/42] vs. 25. 8% [8/31],χ~2= 34. 968,P < 0. 01).( 3) The expression of neovascularization was positive in carotid atherosclerotic plaques. Compared with the metastatic plaques,the positive expression rate of neovascularization in the vulnerable plaques was higher( 95. 2% [40/42]vs. 22. 6% [7/31],χ~2= 41. 060,P < 0. 01).( 4) In carotid atherosclerotic plaques,Hpa and neovascularization expression was mainly located in the fibrous cap and shoulders of the plaques. Conclusions Hpa has a certain role in the progression of advanced atherosclerotic lesions. Hpa and angiogenesis expression in carotid atherosclerotic plaques has a co-regionality.
Objective To investigate the expression characteristics of heparinase( Hpa) and angiogenesis in human carotid atherosclerotic plaques. Methods Fifty-five consecutive patients with atherosclerotic stenosis in internal carotid artery system treated with carotid endarterectomy( atherosclerosis group) at the Department of Neurosurgery,Fuxing Hospital,Capital Medical University from December 2014 to December 2017 were enrolled retrospectively. They were confirmed by imaging methods,such as vascular ultrasound,CT angiography and/or DSA. According to the atherosclerotic histopathological classification method of American Heart Association,the well-defined advanced atherosclerotic plaques( types Ⅳ-Ⅵ)were screened as carotid atherosclerotic plaque specimens( n = 73). According to the morphological classification criteria,73 carotid atherosclerotic plaque specimens were divided into vulnerable plaques( n = 42) and metastatic plaques( n = 31). Autopsy was performed at the Department of Pathology,Peking University Medical School at the same time,and 15 patients without atherosclerotic lesions were identified as non-atherosclerotic group( 15 normal arterial specimens). Immunohistochemistry and immunofluorescence staining were used to analyze the expression characteristics of Hpa and neovascularization in carotid atherosclerotic plaque. Results( 1) There was no Hpa expression in normal arterial tissue; in the carotid atherosclerotic plaque,the positive expression rate of Hpa was 64. 4%( 47/73).( 2) Compared with the metastatic plaques,the positive expression rate of Hpa in the vulnerable plaques increased( 92. 9% [39/42] vs. 25. 8% [8/31],χ~2= 34. 968,P < 0. 01).( 3) The expression of neovascularization was positive in carotid atherosclerotic plaques. Compared with the metastatic plaques,the positive expression rate of neovascularization in the vulnerable plaques was higher( 95. 2% [40/42]vs. 22. 6% [7/31],χ~2= 41. 060,P < 0. 01).( 4) In carotid atherosclerotic plaques,Hpa and neovascularization expression was mainly located in the fibrous cap and shoulders of the plaques. Conclusions Hpa has a certain role in the progression of advanced atherosclerotic lesions. Hpa and angiogenesis expression in carotid atherosclerotic plaques has a co-regionality.
引文
[1]Sakakura K,Nakano M,Otsuka F,et al.Pathophysiology of atherosclerosis plaque progression[J].Heart Lung Circ,2013,22(6):399-411.
[2]Michel JB,Martin-Ventura JL,Nicoletti A,et al.Pathology of human plaque vulnerability:mechanisms and consequences of intraplaque haemorrhages[J].Atherosclerosis,2014,234(2):311-319.
[3]Cicha I,W9rner A,Urschel K,et al.Carotid plaque vulnerability:a positive feedback between hemodynamic and biochemical mechanisms[J].Stroke,2011,42(12):3502-3510.
[4]Di Stefano R,Felice F,Balbarini A.Angiogenesis as risk factor for plaque vulnerability[J].Curr Pharm Des,2009,15(10):1095-1106.
[5]徐斌,张丹,刘兴洲,等.颈动脉粥样硬化斑块内新生血管超声造影特点的初步临床研究[J].中国卒中杂志,2009,4(7):557-561.
[6]孟焱,徐斌,张丹,等.对颈动脉粥样硬化溃疡斑块内超声造影的定量研究[J].中国卒中杂志,2010,5(11):899-903.
[7]Xu B,Xing J,Wu W,et al.Improved plaque neovascularization following 2 year atorvastatin therapy based on contrast enhanced ultrasonography:a pilot study[J].Exp Ther Med,2018,15(5):4491-4497.
[8]Naomoto Y,Gunduz M,Takaoka M,et al.Heparanase promotes angiogenesis through Cox-2 and HIF1 alpha[J].Med Hypotheses,2007,68(1):162-165.
[9]Thompson CA,Purushothaman A,Ramani VC,et al.Heparanase regulates secretion,composition,and function of tumor cell-derived exosomes[J].J Biol Chem,2013,288(14):10093-10099.
[10]Sanderson RD,Elkin M,Rapraeger AC,et al.Heparanase regulation of cancer,autophagy and inflammation:new mechanisms and targets for therapy[J].FEBS J,2017,284(1):42-55.
[11]安琪儿,建平,黄桂香.乙酰肝素酶在子宫内膜异位症中的研究进展[J].疾病监测与控制,2010,4(1):10-11.
[12]Sakakura K,Nakano M,Otsuka F,et al.Pathophysiology of atherosclerosis plaque progression[J].Heart Lung Circ,2013,22(6):399-411.
[13]Blich M,Golan A,Arvatz G,et al.Macrophage activation by heparanase is mediated by TLR-2 and TLR-4 and associates with plaque progressin[J].Arterioscler Thromb Vasc Biol,2013,33(2):e56-e65.
[14]Stary HC,Chandler AB,Dinsmore RE,et al.A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis.A report from the committee on vascular lesions of the council on arteriosclerosis,American Heart Association[J].Circulation,1995,92(5):1355-1374.
[15]Virmani R,Kolodgie FD,Burke AP,et a1.Lessons from sudden coronary death:a comprehensive morphological classification scheme for atherosclerotic lesions[J].Arterioscle Thromb Vasc Biol,2000,20(5):1262-1275.
[16]颈动脉狭窄诊治指南.中华医学会外科学分会血管外科学组[J].中国血管外科杂志(电子版)2017,9(3):169-175.
[17]Naghavi M,Libby P,Falk E,et al.From vulnerable plaque to vulnerable patient:a call for new definitions and risk assessment strategies:PartⅠ[J].Circulation,2003,108(14):1664-1672.
[18]Virmani R,Burke AP,Farb A,et al.Pathology of the vulnerable plaque[J].J Am Coll Cardiol,2006,47(8 Suppl):C13-C18.
[19]Baker AB,Chatzizisis YS,Beigel R,et al.Regulation of heparanase expression in coronary artery disease in diabetic,hyper lipidemic swine[J].Atherosclerosis,2010,213(2):436-442.
[20]HckerU,Nybakken K,Perrimon N.Heparan sulphate proteoglycans:the sweet side of development[J].Nat Rev Mol Cell Biol,2005,6(7):530-541.
[21]Parish CR,Freeman C,Hulett MD.Heparanase:a key enzyme involved in cell invasion[J].Biochim Biophys Acta,2001,1471(3):M99-M108.
[22]Vlodavsky I,Friedmann Y.Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis[J].J Clin Invest,2001,108(3):341-347.
[23]Ilan N,Elkin M,Vlodavsky I.Regulation,function and clinical significance of heparanase in cancer metastasis and angiogenesis[J].Int J Biochem Cell Biol,2006,38(12):2018-2039.
[24]Vlodavsky I,Beckhove P,Lerner I,et al.Significance of heparanase in cancer and inflammation[J].Cancer Microenviron,2012,5(2):115-132.
[25]李娜,徐斌.乙酰肝素酶与动脉粥样硬化[J].国际脑血管病杂志,2013,21(8):634-637.
[26]Madonna R,De Caterina R.Potential roles of vessel wall heparin sulfate proteoglycans in atherosclerosis[J].Vascul Pharmacol,2014,60(2):49-51.
[27]Sukhova GK,Sch9nbeck U,Rabkin E,et al.Evidence for increased collagenolysis by interstitial collagenases-1 and-3in vulnerable human atheromatous plaques[J].Circulation,1999,99(19):2503-2509.
[28]Akbarshahi H,Axelsson JB,Said K,et al.TLR4 dependent heparansulphate-induced pancreatic inflammatory response is IRF3-mediated[J].J Transl Med,2011,9:219.
[29]Axelsson J,Xu D,Kang BN,et al.Inactivation of heparan sulfate 2-O-sulfotransferase accentuates neutrophil infiltration during acute inflammation in mice[J].Blood,2012,120(8):1742-1751.
[30]Vlodavsky I,Iozzo RV,Sanderson RD.Heparanase:multiple functions in inflammation,diabetes and atherosclerosis[J].Matrix Biol,2013,32(5):220-222.
[31]Lu J,Pompili VJ,Das H.Neovascularization and hematopoietic stem cells[J].Cell Biochem Biophys,2013,67(2):235-245.
[32]Michel JB,Delbosc S,Ho-Tin-NoéB,et al.From intraplaque haem orrhages to plaquevulnerability:biologicalconsequencesofintraplaque aemorrhages[J].JCardiovasc Med(Hagerstown),2012,13(10):628-634.
[33]Li J,Li JP,Zhang X,et al.Expression of heparanase in vascular cells and astrocytes of the mouse brain after focal cerebral ischemia[J].Brain Res,2012,1433:137-144.
[34]Zetser A,Bashenko Y,Edovitsky E,et al.Heparanase induces vascular endothelial growth factor expression:correlation with p3 8 phosphorylation levels and Src activation[J].Cancer Res,2006,66(3):1455-1463.
[35]Hong X,Jiang F,Kalkanis SN,et al.Increased chemotactic migration and growth in heparanase-overexpressing human U251n glioma cells[J].J Exp Clin Cancer Res,2008,27:23.
[36]Koole D,Heyligers J,Moll FL,et al.Intraplaque neovascularization and hemorrhage:markers for cardiovascular risk stratification and therapeutic monitoring[J].J Cardiovasc Med(Hagerstown),2012,13(10):635-639.
[2]Michel JB,Martin-Ventura JL,Nicoletti A,et al.Pathology of human plaque vulnerability:mechanisms and consequences of intraplaque haemorrhages[J].Atherosclerosis,2014,234(2):311-319.
[3]Cicha I,W9rner A,Urschel K,et al.Carotid plaque vulnerability:a positive feedback between hemodynamic and biochemical mechanisms[J].Stroke,2011,42(12):3502-3510.
[4]Di Stefano R,Felice F,Balbarini A.Angiogenesis as risk factor for plaque vulnerability[J].Curr Pharm Des,2009,15(10):1095-1106.
[5]徐斌,张丹,刘兴洲,等.颈动脉粥样硬化斑块内新生血管超声造影特点的初步临床研究[J].中国卒中杂志,2009,4(7):557-561.
[6]孟焱,徐斌,张丹,等.对颈动脉粥样硬化溃疡斑块内超声造影的定量研究[J].中国卒中杂志,2010,5(11):899-903.
[7]Xu B,Xing J,Wu W,et al.Improved plaque neovascularization following 2 year atorvastatin therapy based on contrast enhanced ultrasonography:a pilot study[J].Exp Ther Med,2018,15(5):4491-4497.
[8]Naomoto Y,Gunduz M,Takaoka M,et al.Heparanase promotes angiogenesis through Cox-2 and HIF1 alpha[J].Med Hypotheses,2007,68(1):162-165.
[9]Thompson CA,Purushothaman A,Ramani VC,et al.Heparanase regulates secretion,composition,and function of tumor cell-derived exosomes[J].J Biol Chem,2013,288(14):10093-10099.
[10]Sanderson RD,Elkin M,Rapraeger AC,et al.Heparanase regulation of cancer,autophagy and inflammation:new mechanisms and targets for therapy[J].FEBS J,2017,284(1):42-55.
[11]安琪儿,建平,黄桂香.乙酰肝素酶在子宫内膜异位症中的研究进展[J].疾病监测与控制,2010,4(1):10-11.
[12]Sakakura K,Nakano M,Otsuka F,et al.Pathophysiology of atherosclerosis plaque progression[J].Heart Lung Circ,2013,22(6):399-411.
[13]Blich M,Golan A,Arvatz G,et al.Macrophage activation by heparanase is mediated by TLR-2 and TLR-4 and associates with plaque progressin[J].Arterioscler Thromb Vasc Biol,2013,33(2):e56-e65.
[14]Stary HC,Chandler AB,Dinsmore RE,et al.A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis.A report from the committee on vascular lesions of the council on arteriosclerosis,American Heart Association[J].Circulation,1995,92(5):1355-1374.
[15]Virmani R,Kolodgie FD,Burke AP,et a1.Lessons from sudden coronary death:a comprehensive morphological classification scheme for atherosclerotic lesions[J].Arterioscle Thromb Vasc Biol,2000,20(5):1262-1275.
[16]颈动脉狭窄诊治指南.中华医学会外科学分会血管外科学组[J].中国血管外科杂志(电子版)2017,9(3):169-175.
[17]Naghavi M,Libby P,Falk E,et al.From vulnerable plaque to vulnerable patient:a call for new definitions and risk assessment strategies:PartⅠ[J].Circulation,2003,108(14):1664-1672.
[18]Virmani R,Burke AP,Farb A,et al.Pathology of the vulnerable plaque[J].J Am Coll Cardiol,2006,47(8 Suppl):C13-C18.
[19]Baker AB,Chatzizisis YS,Beigel R,et al.Regulation of heparanase expression in coronary artery disease in diabetic,hyper lipidemic swine[J].Atherosclerosis,2010,213(2):436-442.
[20]HckerU,Nybakken K,Perrimon N.Heparan sulphate proteoglycans:the sweet side of development[J].Nat Rev Mol Cell Biol,2005,6(7):530-541.
[21]Parish CR,Freeman C,Hulett MD.Heparanase:a key enzyme involved in cell invasion[J].Biochim Biophys Acta,2001,1471(3):M99-M108.
[22]Vlodavsky I,Friedmann Y.Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis[J].J Clin Invest,2001,108(3):341-347.
[23]Ilan N,Elkin M,Vlodavsky I.Regulation,function and clinical significance of heparanase in cancer metastasis and angiogenesis[J].Int J Biochem Cell Biol,2006,38(12):2018-2039.
[24]Vlodavsky I,Beckhove P,Lerner I,et al.Significance of heparanase in cancer and inflammation[J].Cancer Microenviron,2012,5(2):115-132.
[25]李娜,徐斌.乙酰肝素酶与动脉粥样硬化[J].国际脑血管病杂志,2013,21(8):634-637.
[26]Madonna R,De Caterina R.Potential roles of vessel wall heparin sulfate proteoglycans in atherosclerosis[J].Vascul Pharmacol,2014,60(2):49-51.
[27]Sukhova GK,Sch9nbeck U,Rabkin E,et al.Evidence for increased collagenolysis by interstitial collagenases-1 and-3in vulnerable human atheromatous plaques[J].Circulation,1999,99(19):2503-2509.
[28]Akbarshahi H,Axelsson JB,Said K,et al.TLR4 dependent heparansulphate-induced pancreatic inflammatory response is IRF3-mediated[J].J Transl Med,2011,9:219.
[29]Axelsson J,Xu D,Kang BN,et al.Inactivation of heparan sulfate 2-O-sulfotransferase accentuates neutrophil infiltration during acute inflammation in mice[J].Blood,2012,120(8):1742-1751.
[30]Vlodavsky I,Iozzo RV,Sanderson RD.Heparanase:multiple functions in inflammation,diabetes and atherosclerosis[J].Matrix Biol,2013,32(5):220-222.
[31]Lu J,Pompili VJ,Das H.Neovascularization and hematopoietic stem cells[J].Cell Biochem Biophys,2013,67(2):235-245.
[32]Michel JB,Delbosc S,Ho-Tin-NoéB,et al.From intraplaque haem orrhages to plaquevulnerability:biologicalconsequencesofintraplaque aemorrhages[J].JCardiovasc Med(Hagerstown),2012,13(10):628-634.
[33]Li J,Li JP,Zhang X,et al.Expression of heparanase in vascular cells and astrocytes of the mouse brain after focal cerebral ischemia[J].Brain Res,2012,1433:137-144.
[34]Zetser A,Bashenko Y,Edovitsky E,et al.Heparanase induces vascular endothelial growth factor expression:correlation with p3 8 phosphorylation levels and Src activation[J].Cancer Res,2006,66(3):1455-1463.
[35]Hong X,Jiang F,Kalkanis SN,et al.Increased chemotactic migration and growth in heparanase-overexpressing human U251n glioma cells[J].J Exp Clin Cancer Res,2008,27:23.
[36]Koole D,Heyligers J,Moll FL,et al.Intraplaque neovascularization and hemorrhage:markers for cardiovascular risk stratification and therapeutic monitoring[J].J Cardiovasc Med(Hagerstown),2012,13(10):635-639.