Lgr5调控Wnt/β-Catenin信号通路与心血管疾病研究进展
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摘要
心血管疾病的发病率和死亡率逐年上升,已成为威胁人类健康的重大疾病之一。过去Lgr5-Wnt/β-Catenin信号通路为肿瘤学研究热点。最新研究表明Wnt信号通路与心血管疾病存在密切联系,Lgr5作为Wnt/β-Catenin信号通路受体蛋白亦被认为是心血管疾病潜在分子标记物。本文就Lgr5-Wnt/β-Catenin信号通路与心血管疾病的研究进展作一综述。
The morbidity and mortality of cardiovascular diseases increase year by year, and it has become one of the most important diseases threatening human health. Lgr5-Wnt/β-Catenin signaling pathway has been a hot topic in oncology. The latest research displays that the Wnt signaling pathway is closely related to cardiovascular diseases,as the receptor protein and targetgene of Wnt/β-Catenin singeal,Lgr5 is also considered as the potential molecular marker of cardiovascular diseases.we introduced the Lgr5-Wnt/β-Catenin and overciewed the research progress the relationship between Lgr5-Wnt/β-Catenin and cardiovasular diseases in recent years.
The morbidity and mortality of cardiovascular diseases increase year by year, and it has become one of the most important diseases threatening human health. Lgr5-Wnt/β-Catenin signaling pathway has been a hot topic in oncology. The latest research displays that the Wnt signaling pathway is closely related to cardiovascular diseases,as the receptor protein and targetgene of Wnt/β-Catenin singeal,Lgr5 is also considered as the potential molecular marker of cardiovascular diseases.we introduced the Lgr5-Wnt/β-Catenin and overciewed the research progress the relationship between Lgr5-Wnt/β-Catenin and cardiovasular diseases in recent years.
引文
[1] 陈伟伟, 高润霖, 刘力生,等. 中国心血管病报告2016概要[J]. 中国循环杂志, 2017, 32(6):521-530.
[2] Berndt JD, Moon RT. Cell biology. Making a point with Wnt signals[J]. Science, 2013, 339(6126):1388-1389.
[3] Wu J, Cohen S M. Repression of Teashirt marks the initiation of wing development[J]. Development, 2002, 129(10):2411-2418.
[4] Nusse R. Wnt signaling in disease and in development[J]. Cell Research, 2005, 15(1):28-32.
[5] Chien AJ, Conrad WH, Moon RT. A Wnt survival guide: from flies to human disease[J]. Journal of Investigative Dermatology, 2009, 129(7):1614-1627.
[6] MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases[J]. Developmental Cell, 2009, 17(1):9-26.
[7] Hsu SY,Liang SG,Hsueh AJ.Characterization of two LGR genes homologous to gonadotropin and thyrotropin receptors with extracellular leucine-rich repeats and a G protein-coupled,seven-Transmembrane region[J].Molecular Endocrinology,2009,12(12):1830-1845.
[8] Carmon KS, Gong X, Lin Q, et al. R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/-catenin signaling[J]. Proceedings of the National Academy of Sciences of the United States of America, 2011, 108(28):11452-11457.
[9] De LW, Barker N, Low TY, et al. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling[J]. Nature, 2011, 476(7360):293-297.
[10] Andrei Glinka, Christine Dolde, Nadine Kirsch, et al. LGR4 and LGR5 are R-spondin receptors mediating Wnt/β-catenin and Wnt/PCP signalling[J].EMBO reports,2011, 12(10):1055-1061.
[11] Glinka A, Dolde C, Kirsch N,et al. LGR4 and LGR5 are R-spondin receptors mediating Wnt/β-catenin and Wnt/PCP signalling[J]. Embo Reports, 2011, 12(10):1055-1061.
[12] Birchmeier W. Stem cells: Orphan receptors find a home[J].Nature, 2011, 476(7360):287-288.
[13] Kinzel B, Pikiolek M, Orsini V, et al. Functional roles of Lgr4 and Lgr5 in embryonic gut, kidney and skin development in mice[J]. Developmental Biology, 2014, 390(2):181-190.
[14] Schuijers J, Clevers H. Adult mammalian stem cells: the role of Wnt, Lgr5 and R-spondins[J]. Embo Journal, 2012, 31(31):2685-2696.
[15] Hartogh SCD, Wolstencroft K, Mummery CL, et al.A comprehensive gene expression analysis at sequential stages of in vitro cardiac differentiation from isolated MESP1-expressing-mesoderm progenitors[J]. Scientific Reports, 2016, 19(6):19386-19409.
[16] Shaikh LH, Zhou J, Teo AED, et al. LGR5 Activates Noncanonical Wnt Signaling and Inhibits Aldosterone Production in the Human Adrenal[J]. Journal of Clinical Endocrinology & Metabolism, 2015, 100(6):836-844.
[17] Gelfand BD, Meller J, Pryor AW, et al. Hemodynamic activation of beta-catenin and T-cell-specific transcription factor signaling in vascular endothelium regulates fibronectin expression[J]. Arteriosclerosis Thrombosis & Vascular Biology, 2011, 31(7):1625-1633.
[18] Sumida T, Naito AT, Nomura S, et al. Complement C1q-induced activation of β-catenin signalling causes hypertensive arterial remodelling[J].Nature Communications, 2015, 6(22):6241-6252.
[19] Chen L, Wu Q, Guo F, et al. Expression of Dishevelled-1 in wound healing after acute myocardial infarction: Possible involvement in myofibroblast proliferation and migration[J]. Journal of cellular and molecular medicine, 2004, 8(2):257-264.
[20] Assmus B, Iwasaki M, Sch?chinger V, et al. Acute myocardial infarction activates progenitor cells and increases Wnt signalling in the bone marrow[J].European Heart Journal, 2012, 33(15):1911-1919.
[21] Malekar P, Hagenmueller M, Anyanwu A, et al. Wnt signaling is critical for maladaptive cardiac hypertrophy and accelerates myocardial remodeling[J].Hypertension, 2010, 55(4):939-945.
[22] Tao J, Chen B, Ma Y, et al. FrzA gene protects cardiomyocytes from H. sub.2 O. sub.2-induced oxidative stress through restraining the Wnt/Frizzled pathway[J].Lipids in Health & Disease, 2015, 14(1):1-10.
[23] Barandon L, Casassus F, Leroux L, et al. Secreted frizzled-related protein-1 improves postinfarction scar formation through a modulation of inflammatory response[J].Arteriosclerosis Thrombosis & Vascular Biology, 2011, 31(11):80-87.
[24] He W, Seidman J G. Exogenously administered secreted frizzled related protein 2 (Sfrp2) reduces fibrosis and improves cardiac function in a rat model of myocardial infarction[J]. Proceedings of the National Academy of Sciences of the United States of America, 2010, 107(49):21110-21115.
[25] Min JK, Park H, Choi HJ, et al. The Wnt antagonist Dickkopf2 promotes angiogenesis in rodent and human endothelial cells[J]. Journal of Clinical Investigation, 2011, 121(5):1882-1893.
[26] Bao MW, Cai Z, Zhang XJ, et al. Dickkopf-3 protects against cardiac dysfunction and ventricular remodelling following myocardial infarction[J]. Basic Research in Cardiology, 2015, 110(3):1-17.
[27] Wang L, Hu XB, Zhang W, et al. Dickkopf-1 as a novel predictor is associated with risk stratification by GRACE risk scores for predictive value in patients with acute coronary syndrome: a retrospective research [J].2013, 8(1):54731-54737.
[28] Hahn JY, Cho HJ, Bae JW, et al. Beta-catenin overexpression reduces myocardial infarct size through differential effects on cardiomyocytes and cardiac fibroblasts[J].Journal of Biological Chemistry, 2006, 281(41):30979-30989.
[29] Chen X, Shevtsov SP, Hsich E, et al. The beta-catenin/T-cell factor/lymphocyte enhancer factor signaling pathway is required for normal and stress-induced cardiac hypertrophy[J]. Molecular & Cellular Biology, 2006, 26(12):4462-4473.
[30] Sklepkiewicz P, Shiomi T, Kaur R, et al. Loss of sFRP-1 Leads to Deterioration of Cardiac Function in Mice and Plays a Role in Human Cardiomyopathy[J]. Circulation Heart Failure, 2015, 8(2):623-630.
[31] Duan J, Gherghe C, Liu D, et al. Wnt1/βcatenin injury response activates the epicardium and cardiac fibroblasts to promote cardiac repair[J]. Embo Journal, 2012, 31(2):429-442.
[32] Moon J, Zhou H, Zhang L S, et al. Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist[J]. Proceedings of the National Academy of Sciences of the United States of America, 2017, 114(7):1649-1654.
[33] Bastakoty D, Saraswati S, Joshi P, et al. Temporary, Systemic Inhibition of the Wnt/β-Catenin Pathway promotes Regenerative Cardiac Repair following Myocardial Infarct[J]. Cell Stem Cells Regen Med, 2016, 2(2): 1-27.
[34] Xiang FL, Fang M, Yutzey KE. Loss of β-catenin in resident cardiac fibroblasts attenuates fibrosis induced by pressure overload in mice[J]. Nature Communications, 2017, 8(1):712-725.
[35] Basso C, Bauce B, Corrado D, et al. Pathophysiology of arrhythmogenic cardiomyopathy[J]. Nature Reviews Cardiology, 2012, 9(4):223-233.
[36] Priori SG, Santiago DJ.Arrhythmogenic Cardiomyopathy: Pathophysiology Beyond Cardiac Myocytes[J]. Circulation Research, 2017, 121(12):1296-1298.
[37] Hoorntje ET, Te Rijdt WP, James CA, et al. Arrhythmogenic cardiomyopathy: pathology, genetics, and concepts in pathogenesis[J]. Cardiovascular Research, 2017, 113(12):1521-1531.
[38] Nava A, Thiene G, Canciani B, et al. Familial occurrence of right ventricular dysplasia: a study involving nine families[J].Journal of the American College of Cardiology,1988, 12(5):1222-1228.
[39] Ross SE, Hemati N, Longo KA, et al. Inhibition of Adipogenesis by Wnt Signaling[J]. Science, 2000, 289(5481):950-953.
[40] Zhang H, Liu S, Dong T, et al.Profiling of differentially expressed microRNAs in arrhythmogenic right ventricular cardiomyopathy[J]. Scientific Reports, 2016, 16(6):1-6.
[2] Berndt JD, Moon RT. Cell biology. Making a point with Wnt signals[J]. Science, 2013, 339(6126):1388-1389.
[3] Wu J, Cohen S M. Repression of Teashirt marks the initiation of wing development[J]. Development, 2002, 129(10):2411-2418.
[4] Nusse R. Wnt signaling in disease and in development[J]. Cell Research, 2005, 15(1):28-32.
[5] Chien AJ, Conrad WH, Moon RT. A Wnt survival guide: from flies to human disease[J]. Journal of Investigative Dermatology, 2009, 129(7):1614-1627.
[6] MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases[J]. Developmental Cell, 2009, 17(1):9-26.
[7] Hsu SY,Liang SG,Hsueh AJ.Characterization of two LGR genes homologous to gonadotropin and thyrotropin receptors with extracellular leucine-rich repeats and a G protein-coupled,seven-Transmembrane region[J].Molecular Endocrinology,2009,12(12):1830-1845.
[8] Carmon KS, Gong X, Lin Q, et al. R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/-catenin signaling[J]. Proceedings of the National Academy of Sciences of the United States of America, 2011, 108(28):11452-11457.
[9] De LW, Barker N, Low TY, et al. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling[J]. Nature, 2011, 476(7360):293-297.
[10] Andrei Glinka, Christine Dolde, Nadine Kirsch, et al. LGR4 and LGR5 are R-spondin receptors mediating Wnt/β-catenin and Wnt/PCP signalling[J].EMBO reports,2011, 12(10):1055-1061.
[11] Glinka A, Dolde C, Kirsch N,et al. LGR4 and LGR5 are R-spondin receptors mediating Wnt/β-catenin and Wnt/PCP signalling[J]. Embo Reports, 2011, 12(10):1055-1061.
[12] Birchmeier W. Stem cells: Orphan receptors find a home[J].Nature, 2011, 476(7360):287-288.
[13] Kinzel B, Pikiolek M, Orsini V, et al. Functional roles of Lgr4 and Lgr5 in embryonic gut, kidney and skin development in mice[J]. Developmental Biology, 2014, 390(2):181-190.
[14] Schuijers J, Clevers H. Adult mammalian stem cells: the role of Wnt, Lgr5 and R-spondins[J]. Embo Journal, 2012, 31(31):2685-2696.
[15] Hartogh SCD, Wolstencroft K, Mummery CL, et al.A comprehensive gene expression analysis at sequential stages of in vitro cardiac differentiation from isolated MESP1-expressing-mesoderm progenitors[J]. Scientific Reports, 2016, 19(6):19386-19409.
[16] Shaikh LH, Zhou J, Teo AED, et al. LGR5 Activates Noncanonical Wnt Signaling and Inhibits Aldosterone Production in the Human Adrenal[J]. Journal of Clinical Endocrinology & Metabolism, 2015, 100(6):836-844.
[17] Gelfand BD, Meller J, Pryor AW, et al. Hemodynamic activation of beta-catenin and T-cell-specific transcription factor signaling in vascular endothelium regulates fibronectin expression[J]. Arteriosclerosis Thrombosis & Vascular Biology, 2011, 31(7):1625-1633.
[18] Sumida T, Naito AT, Nomura S, et al. Complement C1q-induced activation of β-catenin signalling causes hypertensive arterial remodelling[J].Nature Communications, 2015, 6(22):6241-6252.
[19] Chen L, Wu Q, Guo F, et al. Expression of Dishevelled-1 in wound healing after acute myocardial infarction: Possible involvement in myofibroblast proliferation and migration[J]. Journal of cellular and molecular medicine, 2004, 8(2):257-264.
[20] Assmus B, Iwasaki M, Sch?chinger V, et al. Acute myocardial infarction activates progenitor cells and increases Wnt signalling in the bone marrow[J].European Heart Journal, 2012, 33(15):1911-1919.
[21] Malekar P, Hagenmueller M, Anyanwu A, et al. Wnt signaling is critical for maladaptive cardiac hypertrophy and accelerates myocardial remodeling[J].Hypertension, 2010, 55(4):939-945.
[22] Tao J, Chen B, Ma Y, et al. FrzA gene protects cardiomyocytes from H. sub.2 O. sub.2-induced oxidative stress through restraining the Wnt/Frizzled pathway[J].Lipids in Health & Disease, 2015, 14(1):1-10.
[23] Barandon L, Casassus F, Leroux L, et al. Secreted frizzled-related protein-1 improves postinfarction scar formation through a modulation of inflammatory response[J].Arteriosclerosis Thrombosis & Vascular Biology, 2011, 31(11):80-87.
[24] He W, Seidman J G. Exogenously administered secreted frizzled related protein 2 (Sfrp2) reduces fibrosis and improves cardiac function in a rat model of myocardial infarction[J]. Proceedings of the National Academy of Sciences of the United States of America, 2010, 107(49):21110-21115.
[25] Min JK, Park H, Choi HJ, et al. The Wnt antagonist Dickkopf2 promotes angiogenesis in rodent and human endothelial cells[J]. Journal of Clinical Investigation, 2011, 121(5):1882-1893.
[26] Bao MW, Cai Z, Zhang XJ, et al. Dickkopf-3 protects against cardiac dysfunction and ventricular remodelling following myocardial infarction[J]. Basic Research in Cardiology, 2015, 110(3):1-17.
[27] Wang L, Hu XB, Zhang W, et al. Dickkopf-1 as a novel predictor is associated with risk stratification by GRACE risk scores for predictive value in patients with acute coronary syndrome: a retrospective research [J].2013, 8(1):54731-54737.
[28] Hahn JY, Cho HJ, Bae JW, et al. Beta-catenin overexpression reduces myocardial infarct size through differential effects on cardiomyocytes and cardiac fibroblasts[J].Journal of Biological Chemistry, 2006, 281(41):30979-30989.
[29] Chen X, Shevtsov SP, Hsich E, et al. The beta-catenin/T-cell factor/lymphocyte enhancer factor signaling pathway is required for normal and stress-induced cardiac hypertrophy[J]. Molecular & Cellular Biology, 2006, 26(12):4462-4473.
[30] Sklepkiewicz P, Shiomi T, Kaur R, et al. Loss of sFRP-1 Leads to Deterioration of Cardiac Function in Mice and Plays a Role in Human Cardiomyopathy[J]. Circulation Heart Failure, 2015, 8(2):623-630.
[31] Duan J, Gherghe C, Liu D, et al. Wnt1/βcatenin injury response activates the epicardium and cardiac fibroblasts to promote cardiac repair[J]. Embo Journal, 2012, 31(2):429-442.
[32] Moon J, Zhou H, Zhang L S, et al. Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist[J]. Proceedings of the National Academy of Sciences of the United States of America, 2017, 114(7):1649-1654.
[33] Bastakoty D, Saraswati S, Joshi P, et al. Temporary, Systemic Inhibition of the Wnt/β-Catenin Pathway promotes Regenerative Cardiac Repair following Myocardial Infarct[J]. Cell Stem Cells Regen Med, 2016, 2(2): 1-27.
[34] Xiang FL, Fang M, Yutzey KE. Loss of β-catenin in resident cardiac fibroblasts attenuates fibrosis induced by pressure overload in mice[J]. Nature Communications, 2017, 8(1):712-725.
[35] Basso C, Bauce B, Corrado D, et al. Pathophysiology of arrhythmogenic cardiomyopathy[J]. Nature Reviews Cardiology, 2012, 9(4):223-233.
[36] Priori SG, Santiago DJ.Arrhythmogenic Cardiomyopathy: Pathophysiology Beyond Cardiac Myocytes[J]. Circulation Research, 2017, 121(12):1296-1298.
[37] Hoorntje ET, Te Rijdt WP, James CA, et al. Arrhythmogenic cardiomyopathy: pathology, genetics, and concepts in pathogenesis[J]. Cardiovascular Research, 2017, 113(12):1521-1531.
[38] Nava A, Thiene G, Canciani B, et al. Familial occurrence of right ventricular dysplasia: a study involving nine families[J].Journal of the American College of Cardiology,1988, 12(5):1222-1228.
[39] Ross SE, Hemati N, Longo KA, et al. Inhibition of Adipogenesis by Wnt Signaling[J]. Science, 2000, 289(5481):950-953.
[40] Zhang H, Liu S, Dong T, et al.Profiling of differentially expressed microRNAs in arrhythmogenic right ventricular cardiomyopathy[J]. Scientific Reports, 2016, 16(6):1-6.