血管生成素-Tie通路在冠心病中的作用机制及意义
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摘要
冠心病作为常见的心血管病,其患病率和死亡率仍呈上升趋势,冠心病的防治已成为全社会研究的重要课题。从血管新生的角度研究冠状动脉粥样硬化、急性心肌梗死、心梗所致心源性休克等的发病机制具有很大的临床意义,而治疗性血管新生可为冠心病患者提供新的治疗选择。血管生成素(angiopoietins,Angs)-Tie通路是参与血管新生过程的重要信号传导通路,主要包括Ang1、Ang2、Ang3、Ang4及其受体Tie1、Tie2。目前研究较多的有Ang1、Ang2和Tie2,其中Ang1-Tie2主要维持脉管系统稳定,Ang2-Tie2与血管重塑密切相关。动脉粥样硬化病变中的斑块生长和斑块不稳定都涉及到了新血管形成。Angs是从斑块形成的初始阶段到急性心血管事件发生过程中的关键因素。Angs在不稳定型心绞痛、急性心肌梗死、心梗所致心源性休克的发病过程中都起到了关键作用,Angs还可以作为上述疾病发生发展的新指标。在治疗方面,Angs-Tie通路是冠状动脉粥样硬化早期预防,心梗后改善心脏灌注及功能,和促进侧支循环建立等的潜在治疗靶点。本文将对Angs-Tie通路在冠心病及相关疾病中的作用及临床意义作一综述。
As a common cardiovascular disease, coronary heart disease(CHD) continues to be the leading cause of mortality as well as morbidity. The prevention and treatment of coronary heart disease(CHD) has become an important topic in the whole society. It is of great clinical significance to associate angiogenesis with the pathogenesis of coronary atherosclerosis, acute myocardial infarction(AMI), and cardiogenic shock after AMI. Therapeutic angiogenesis may provide new treatment options for patients with coronary heart disease. Angiopoietin(Angiopoietins, Angs)-Tie pathway is an important signal transduction pathway involved in angiogenesis, including Ang1, Ang2, Ang3, Ang4 and its receptor Tie1, Tie2. At present, there are more studies on Ang1, Ang2 and Tie2, in which Ang1-Tie2 mainly maintains vascular system stability, and Ang2-Tie2 is closely related to vascular remodeling. Both plaque growth and instability in atherosclerosis involve neovascularization. Angs is a key factor from the initial stage of plaque formation to the occurrence of acute cardiovascular events. Angs also plays a key role in the pathogenesis of unstable angina pectoris cardiogenic, AMI, and cardiogenic shock after AMI. Angs can become a new indicator of the occurrence and development of these diseases. In treatment, Angs-Tie pathway is a potential therapeutic target for early prevention of coronary atherosclerosis, improvement of cardiac perfusion and function after myocardial infarction, and promotion of collateral circulation. This article reviews the mechanism and significance of Angs-Tie pathway in coronary heart disease.
As a common cardiovascular disease, coronary heart disease(CHD) continues to be the leading cause of mortality as well as morbidity. The prevention and treatment of coronary heart disease(CHD) has become an important topic in the whole society. It is of great clinical significance to associate angiogenesis with the pathogenesis of coronary atherosclerosis, acute myocardial infarction(AMI), and cardiogenic shock after AMI. Therapeutic angiogenesis may provide new treatment options for patients with coronary heart disease. Angiopoietin(Angiopoietins, Angs)-Tie pathway is an important signal transduction pathway involved in angiogenesis, including Ang1, Ang2, Ang3, Ang4 and its receptor Tie1, Tie2. At present, there are more studies on Ang1, Ang2 and Tie2, in which Ang1-Tie2 mainly maintains vascular system stability, and Ang2-Tie2 is closely related to vascular remodeling. Both plaque growth and instability in atherosclerosis involve neovascularization. Angs is a key factor from the initial stage of plaque formation to the occurrence of acute cardiovascular events. Angs also plays a key role in the pathogenesis of unstable angina pectoris cardiogenic, AMI, and cardiogenic shock after AMI. Angs can become a new indicator of the occurrence and development of these diseases. In treatment, Angs-Tie pathway is a potential therapeutic target for early prevention of coronary atherosclerosis, improvement of cardiac perfusion and function after myocardial infarction, and promotion of collateral circulation. This article reviews the mechanism and significance of Angs-Tie pathway in coronary heart disease.
引文
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[26] EHRLICH K C,LACEY M,EHRLICH M.Tissue-specific epigenetics of atherosclerosis-related ANGPT and ANGPTL genes[J].Epigenomics,2019,11(2):169-186.
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[32] LIU K L,LIN S M,CHANG C H,et al.Plasma angiopoietin-1 level,left ventricular ejection fraction,and multivessel disease predict development of 1-year major adverse cardiovascular events in patients with acute ST elevation myocardial infarction - a pilot study[J].Int J Cardiol,2015,182:155-160.
[33] CAO S,ZHOU Q,CHEN J L,et al.Comparison of intracoronary and intravenous ultrasound-targeted microbubble destruction-mediated Ang1 gene transfection on left ventricular remodeling in canines with acute myocardial infarction[J].J Cardiovasc Pharmacol,2017,70(1):25-33.
[34] OLIVEIRA A L A,SCHEFFER J P,MARKOSKI M,et al.Vascular endothelial growth factor association with angiopoietin 1 promotes improvement in ventricular function after ischemic cardiomyopathy induced in mini pigs[J].Acta Cir Bras,2018,33(4):386-395.
[35] LINK A,P?SS J,RBAH R,et al.Circulating angiopoietins and cardiovascular mortality in cardiogenic shock[J].Eur Heart J,2013,34(22):1651-1662.
[36] P?SS J,FUERNAU G,DENKS D,et al.Angiopoietin-2 in acute myocardial infarction complicated by cardiogenic shock-a biomarker substudy of the IABP-SHOCK Ⅱ-Trial[J].Eur J Heart Failure,2015,17(11):1152-1160.
[37] QIN Q,QIAN J,MA J,et al.Relationship between thrombospondin-1,endostatin,angiopoietin-2,and coronary collateral development in patients with chronic total occlusion[J].Medicine(Baltimore),2016,95(33):e4524.
[2] EKLUND L,SAHARINEN P.Angiopoietin signaling in the vasculature[J].Exp Cell Res,2013,319(9):1271-1280.
[3] EKLUND L,KANGAS J,SAHARINEN P.Angiopoietin-Tie signalling in the cardiovascular and lymphatic systems[J].Clin Sci(Lond),2017,131(1):87-103.
[4] KORHONEN E A,LAMPINEN A,GIRI H,et al.Tie1 controls angiopoietin function in vascular remodeling and inflammation[J].J Clin Invest,2016,126(9):3495-3510.
[5] KOH G Y.Orchestral actions of angiopoietin-1 in vascular regeneration[J].Trends Mol Med,2013,19(1):31-39.
[6] PARIKH S M.Angiopoietins and Tie2 in vascular inflammation[J].Curr Opin Hematol,2017,24(5):432-438.
[7] PARIKH S M.The Angiopoietin-Tie2 signaling axis in systemic inflammation[J].J Am Soc Nephrol,2017,28(7):1973-1982.
[8] KESLER C T,Pereira E R,Cui C H,et al.Angiopoietin-4 increases permeability of blood vessels and promotes lymphatic dilation[J].FASEB J,2015,29(9):3668-3677.
[9] DALTON A C,SHLAMKOVITCH T,PAPO N,et al.Constitutive association of Tie1 and Tie2 with endothelial integrins is functionally modulated by angiopoietin-1 and fibronectin[J].PLoS One,2016,11(10):e163732.
[10] GHOSH C C,THAMM K,BERGHELLI A V,et al.Drug repurposing screen identifies foxo1-dependent angiopoietin-2 regulation in sepsis[J].Crit Care Med,2015,43(7):e230-e240.
[11] 王锡煌,王挹青,宋晶金.血管生成素1通过核因子κB传导通路调节内皮祖细胞炎症因子表达[J].中国动脉硬化杂志,2012,20(4):309-314.
[12] YU X,SEEGAR T C,DALTON A C,et al.Structural basis for angiopoietin-1-mediated signaling initiation[J].Proc Natl Acad Sci U S A,2013,110(18):7205-7210.
[13] MIRANDO AC ,SHEN J,SILVA R L E,et al.A collagen IV-derived peptide disrupts alpha5beta1 integrin and potentiates Ang2/Tie2 signaling[J].JCI Insight,2019,4(4):122043.
[14] KORHONEN E A,LAMPINEN A,GIRI H,et al.Tie1 controls angiopoietin function in vascular remodeling and inflammation[J].J Clin Invest,2016,126(9):3495-3510.
[15] KIM M,ALLEN B,KORHONEN E A,et al.Opposing actions of angiopoietin-2 on Tie2 signaling and FOXO1 activation[J].J Clin Invest,2016,126(9):3511-3525.
[16] LE C T,LAIDLAW G,MOREHOUSE C A,et al.Synergistic actions of blocking angiopoietin-2 and tumor necrosis factor-α in suppressing remodeling of blood vessels and lymphatics in airway inflammation[J].Am J Pathol,2015,185(11):2949-2968.
[17] SOUMA T,THOMSON B R,HEINEN S,et al.Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP[J].Proc Natl Acad Sci U S A,2018,115(6):1298-1303.
[18] 庹勤慧,廖端芳.促血管生成素1/促血管生成素2的比值与血管病变的关系[J].中国动脉硬化杂志,2009,17(5):414-416.
[19] HAKANPAA L,SIPILA T,LEPPANEN V M,et al.Endothelial destabilization by angiopoietin-2 via integrin beta1 activation[J].Nat Commun,2015,6:5962.
[20] LEE S J,LEE C K,KANG S,et al.Angiopoietin-2 exacerbates cardiac hypoxia and inflammation after myocardial infarction[J].J Clin Invest,2018,128(11):5018-5033.
[21] CAMARé C,PUCELLE M,NèGRE-SALVAYRE A,et al.Angiogenesis in the atherosclerotic plaque[J].Redox biol,2017,12:18-34.
[22] WU H,SHOU X,LIANG L,et al.Correlation between plasma angiopoietin-1,angiopoietin-2 and matrix metalloproteinase-2 in coronary heart disease[J].Arch Med Sci,2016,12(6):1214-1219.
[23] FUJISAWA T,WANG K,NIU X L,et al.Angiopoietin-1 promotes atherosclerosis by increasing the proportion of circulating Gr1+ monocytes[J].Cardiovasc Res,2017,113(1):81-89.
[24] THEELEN T L,LAPPALAINEN J P,SLUIMER J C,et al.Angiopoietin-2 blocking antibodies reduce early atherosclerotic plaque development in mice[J].Atherosclerosis,2015,241(2):297-304.
[25] YU H,MORAN C S,TROLLOPE A F,et al.Angiopoietin-2 attenuates angiotensin II-induced aortic aneurysm and atherosclerosis in apolipoprotein E-deficient mice[J].Sci Rep,2016,6:35190.
[26] EHRLICH K C,LACEY M,EHRLICH M.Tissue-specific epigenetics of atherosclerosis-related ANGPT and ANGPTL genes[J].Epigenomics,2019,11(2):169-186.
[27] YANG X,ZHANG H,SHI Y,et al.Association of serum angiopoietin-2 with malnutrition,inflammation,atherosclerosis and valvular calcification syndrome and outcome in peritoneal dialysis patients:a prospective cohort study[J].J Transl Med,2018,16(1):312.
[28] JIAN W,LI L,WEI X M,et al.Prognostic value of angiopoietin-2 for patients with coronary heart disease after elective PCI[J].Medicine (Baltimore),2019,98(5):e14216.
[29] ZENG Z Y,GUI C,LI L,et al.Effects of percutaneous coronary intervention on serum angiopoietin-2 in patients with coronary heart disease[J].Chin Med J (Engl),2016,129(6):631-635.
[30] LIU K L,LEE K T,CHANG C H,et al.Elevated plasma thrombomodulin and angiopoietin-2 predict the development of acute kidney injury in patients with acute myocardial infarction[J].Crit Care,2014,18(3):R100.
[31] JIAN W,LI L,WEI X M,et al.Serum angiopoietin-2 concentrations of post-PCI are correlated with the parameters of renal function in patients with coronary artery disease[J].Medicine(Baltimore),2019,98(1):e13960.
[32] LIU K L,LIN S M,CHANG C H,et al.Plasma angiopoietin-1 level,left ventricular ejection fraction,and multivessel disease predict development of 1-year major adverse cardiovascular events in patients with acute ST elevation myocardial infarction - a pilot study[J].Int J Cardiol,2015,182:155-160.
[33] CAO S,ZHOU Q,CHEN J L,et al.Comparison of intracoronary and intravenous ultrasound-targeted microbubble destruction-mediated Ang1 gene transfection on left ventricular remodeling in canines with acute myocardial infarction[J].J Cardiovasc Pharmacol,2017,70(1):25-33.
[34] OLIVEIRA A L A,SCHEFFER J P,MARKOSKI M,et al.Vascular endothelial growth factor association with angiopoietin 1 promotes improvement in ventricular function after ischemic cardiomyopathy induced in mini pigs[J].Acta Cir Bras,2018,33(4):386-395.
[35] LINK A,P?SS J,RBAH R,et al.Circulating angiopoietins and cardiovascular mortality in cardiogenic shock[J].Eur Heart J,2013,34(22):1651-1662.
[36] P?SS J,FUERNAU G,DENKS D,et al.Angiopoietin-2 in acute myocardial infarction complicated by cardiogenic shock-a biomarker substudy of the IABP-SHOCK Ⅱ-Trial[J].Eur J Heart Failure,2015,17(11):1152-1160.
[37] QIN Q,QIAN J,MA J,et al.Relationship between thrombospondin-1,endostatin,angiopoietin-2,and coronary collateral development in patients with chronic total occlusion[J].Medicine(Baltimore),2016,95(33):e4524.