泛素-蛋白酶体系统在心血管疾病中的研究进展
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摘要
泛素-蛋白酶体系统(UPS)是真核细胞中蛋白质代谢和蛋白质质量控制重要系统,泛素分子主要通过泛素活化酶、泛素偶联酶、泛素结合酶以及泛素-蛋白连接酶与靶蛋白结合形成多泛素链,从而将底物蛋白泛素化并降解。在心肌细胞肥大和血管平滑肌细胞增殖中通过调节蛋白质合成而控制细胞生长的机制已经被广泛研究,但内源性蛋白在心血管系统中的降解受到的关注较少。UPS负责70%~90%内源性蛋白质的降解,其在多种血管病变的病理生理学过程如氧化应激、炎症、泡沫细胞形成以及动脉粥样硬化的过程起着核心作用,并通过靶向降解信号和结构蛋白影响心脏细胞的结构和功能,参与了心肌病和心力衰竭的发生。
Ubiquitin-proteasome system( UPS) is an important system for protein metabolism and protein quality control in eukaryotic cells. Ubiquitin molecules mainly bind to target proteins through ubiquitin-activating enzyme,ubiquitin-coupled enzyme,ubiquitin-conjugating enzyme and ubiquitin-protein ligase to form polyubiquitin chain,consquently ubiquitinate and degrade the substrate proteins. Whereas the mechanisms controlling cellular growth through protein synthesis have been investigated widely in the terms of cardiac cell hypertrophy and vascular smooth muscle cell proliferation,however,less attention has been paid to the degradation of endogenous proteins in the cardiovascular system. The UPS is responsible for the degradation of 70%-90% endogenous proteins and plays a central role in pathophysiological processes that are very important for vascular diseases including oxidative stress,inflammation,the production of foam cells,and atherosclerosis,and participates in the cardiomyopathy and heart failure by targeted degradation of signaling protein and constitutive protein which affect the structure and function of the cells of heart.
Ubiquitin-proteasome system( UPS) is an important system for protein metabolism and protein quality control in eukaryotic cells. Ubiquitin molecules mainly bind to target proteins through ubiquitin-activating enzyme,ubiquitin-coupled enzyme,ubiquitin-conjugating enzyme and ubiquitin-protein ligase to form polyubiquitin chain,consquently ubiquitinate and degrade the substrate proteins. Whereas the mechanisms controlling cellular growth through protein synthesis have been investigated widely in the terms of cardiac cell hypertrophy and vascular smooth muscle cell proliferation,however,less attention has been paid to the degradation of endogenous proteins in the cardiovascular system. The UPS is responsible for the degradation of 70%-90% endogenous proteins and plays a central role in pathophysiological processes that are very important for vascular diseases including oxidative stress,inflammation,the production of foam cells,and atherosclerosis,and participates in the cardiomyopathy and heart failure by targeted degradation of signaling protein and constitutive protein which affect the structure and function of the cells of heart.
引文
[1]Willis MS,Patterson C.Into the heart:The emerging role of the ubiquitin-proteasome system[J].J Mol Cell Cardiol,2006,41(4):567-579.
[2]Li J,Horak KM,Su H,et al.Enhancement of proteasomal function protects against cardiac proteinopathy and ischemia/reperfusion injury in mice[J].J Clin Invest,2011,121(9):3689-3700.
[3]Razeghi P,Baskin KK,Sharma S,et al.Atrophy,hypertrophy,and hypoxemia induce transcriptional regulators of the ubiquitin proteasome system in the rat heart[J].Biochem Biophys Res Commun,2006,342(2):361-364.
[4]Chen Q,Liu JB,Horak KM,et al.Intrasarcoplasmic amyloidosis impairs proteolytic function of proteasomes in cardiomyocytes by compromising substrate uptake[J].Circ Res,2005,97(10):1018-1026.
[5]Wang X,Pattison JS,Su H.Posttranslational modification and quality control[J].Circ Res,2013,112(2):367-381.
[6]Willis MS,Rojas M,Li L,et al.Muscle ring finger 1 mediates cardiac atrophy in vivo[J].Am J Physiol Heart Circ Physiol,2009,296(4):H997-1006.
[7]Powell SR,Herrmann J,Lerman A.The ubiquitin-proteasome system and cardiovascular disease[J].Prog Mol Biol Transl Sci,2012,109:295-346.
[8]Wang X,Terpstra EJ.Ubiquitin receptors and protein quality control[J].J Mol Cell Cardiol,2013,55:73-84.
[9]Powell SR.The ubiquitin-proteasome system in cardiac physiology and pathology[J].Am J Physiol Heart Circ Physiol,2006,291(1):H1-19.
[10]Herrmann J,Lerman LO,Lerman A.Ubiquitin and ubiquitin-like proteins in protein regulation[J].Circ Res,2007,100(9):1276-1291.
[11]Powers ET,Balch WE.Diversity in the origins of proteostasis networks-adriver for protein function in evolution[J].Nat Rev Mol Cell Biol,2013,14(4):237-248.
[12]Calamini B,Morimoto RI.Protein homeostasis as a therapeutic target for diseases of protein conformation[J].Curr Top Med Chem,2012,12(22):2623-2640.
[13]Park C,Cuervo AM.Selective autophagy Talking with the UPS[J].Cell Biochem Biophys,2013,67(1):3-13.
[14]Su H,Wang X.The ubiquitin-proteasome system in cardiac proteinopathy:A quality control perspective[J].Cardiovasc Res,2010,85(2):253-262.
[15]Bhuiyan MS,Pattison JS,Osinska H,et al.Ehanced autophagy ameliorates cardiac proteinopathy[J].J Clin Invest,2013,123(12):5284-5297.
[16]Drews O,Wildgruber R,Zong C,et al.Mammalian proteasome subpopulations with distinct molecular compositions and proteolytic activities[J].Mol Cell Proteomics,2007,6(11):2021-2031.
[17]Bedford L,Lowe J,Dick LR,et al.Ubiquitin-like protein conjugation and the ubiquitin-proteasome system as drug targets[J].Nat Rev Drug Discov,2011,10(1):29-46.
[18]Ashrafian H,Mc Kenna WJ,Watkins H.Disease pathways and novel therapeutic targets in hypertrophic cardiomyopathy[J].Circ Res,2011,109(1):86-96.
[19]Willis MS,Bevilacqua A,Pulinilkunnil T,et al.The role of ubiquitin ligases in cardiac disease[J].J Mol Cell Cardiol,2014,6(71):43-53.
[20]Bahrudin U,Morisaki H,Morisaki T,et al.Ubiquitin-proteasome system impairment caused by a missense cardiac myosin-binding protein C mutation and associated with cardiac dysfunction in hypertrophic cardiomyopathy[J].J Mol Biol,2008,384(4):896-907.
[21]Predmore JM,Wang P,Davis F,et al.Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies[J].Circulation,2010,121(8):997-1004.
[22]Galasso G,De Rosa R,Piscione F,et al.Myocardial expression of FOXO3a-Atrogin-1 pathway in human heart failure[J].Eur J Heart Fail,2010,12(12):1290-1296.
[23]Hein S,Amon E,Kostin S,et al.Progression from compensated hypertrophy to failure in the pressure-overloaded human heart:Structural deterioration and compensatory mechanisms[J].Circulation,2003,107(7):984-991.
[24]Weekes J,Morrison K,Mullen A,et al.Hyperubiquitination of proteins in dilated cardiomyopathy[J].Proteomics,2003,3(2):208-216.
[25]Birks EJ,Latif N,Enesa K,et al.Elevated p53 expression is associated with dysregulation of the ubiquitin-proteasome system in dilated cardiomyopathy[J].Cardiovasc Res,2008,79(3):472-480.
[26]Bennett EJ,Shaler TA,Woodman B,et al.Global changes to the ubiquitin system in Huntington's disease[J].Nature,2007,448(7154):704-708.
[27]Clague MJ,UrbéS.Ubiquitin:Same molecule,different degradation pathways[J].Cell,2010,143(5):682-685.
[28]Lee DY,Brown EJ.Ubiquilins in the crosstalk among proteolytic pathways[J].Biol Chem,2012,393(6):441-447.
[29]Kostin S,Pool L,Elssser A,et al.Myocytes die by multiple mechanisms in failing human hearts[J].Circ Res,2003,92(7):715-724.
[30]Kassiotis C,Ballal K,Wellnitz K,et al.Markets of autophagy are downregulated in failing human heart after mechanical unloading[J].Circulation,2009,120(11 Suppl):S191-197.
[31]Liu J,Chen Q,Huang W,et al.Impairment of the ubiquitin-proteasome system in desminopathy mouse hearts[J].FASEB J,2006,20(2):362-364.
[32]Liu J,Tang M,Mestril R,et al.Aberrant protein aggregation is essential for amutant desmin to impair the proteolytic function of the ubiquitin-proteasome system in cardiomyocytes[J].J Mol Cell Cardiol,2006,40(4):451-454.
[33]Tian Z,Zheng H,Li J,et al.Genetically induced moderate inhibition of the proteasome in cardiomyocytes exacerbates myocardial ischemia-reperfusion injury in mice[J].Circ Res,2012,111(5):532-542.
[34]Herrmann J,Wohlert C,Saguner AM,et al.Primary proteasome inhibition results in cardiac dysfunction[J].Eur J Heart Fail,2013,15(6):614-623.
[35]Huber EM,Basler M,Schwab R,et al.Immuno-and constitutive proteasome crystal structures reveal differences in substrate and inhibitor specificity[J].Cell,2012,148(4):727-738.
[36]Takami Y,Nakagami H,Morishita R,et al.Potential role of CYLD(Cylindromatosis)as a deubiquitinating enzyme in vascular cells[J].Am J Pathol,2008,172(3):818-829.
[37]Herrmann J,Lerman LO,Lerman A.On to the road to degradation:Atherosclerosis and the proteasome[J].Cardiovasc Res,2010,85(2):291-302.
[38]Xia T,Dimitropoulou C,Zeng J,et al.Chaperone-dependent E3ligase CHIP ubiquitinates and mediates proteasomal degradation of soluble guanylyl cyclase[J].Am J Physiol Heart Circ Physiol,2007,293(5):H3080-3087.
[39]Jiang G,Li T,Qiu Y,et al.RNA interference for HIF-1alpha inhibits foam cells formation in vitro[J].Eur J Pharmacol,2007,562(3):183-190.
[40]Diebold I,Djordjevic T,Hess J,et al.Rac-1 promotes pulmonary artery smooth muscle cell proliferation by upregulation of plasminogen activator inhibitor-1:Role of NF kappa B-dependent hypoxia-inducible factor-1alpha transcription[J].Thromb Haemost,2008,100(6):1021-1028.
[41]Hermann J,Gulati R,Napoli C,et al.Oxidative stress-related increase in ubiquitination in early coronary atherogenesis[J].FASEB J,2003,17(12):1730-1732.
[42]Pashevin DA,Tumanovska LV,Dosenko VE,et al.Antiatherogenic effect of quercetin is mediated by proteasome inhibition in the aorta and circulating leukocytes[J].Pharmacol Rep,2011,63(4):1009-1018.
[43]Weber C,Zernecke A,Libby P.The multifaceted contributions of leukocyte subsets to atherosclerosis:Lessons from mouse models[J].Nat Rev Immunol,2008,8(10):802-815.
[44]Zhao JF,Ching LC,Huang YC,et al.Molecular mechanism of curcumin on the suppression of cholesterol accumulation in macrophage foam cells and atherosclerosis[J].Mol Nutr Food Res,2012,56(5):691-701.
[45]Wang Z,Guo D,Yang B,et al.Integrated analysis of microarray data of atherosclerotic plaques:Modulation of the ubiquitin-proteasome system[J].PLo S One,2014,9(10):e110288.
[46]Düwel M,Welteke V,Oeckinghaus A,et al.A20 negatively regulates T cell receptor signaling to NF-kappa B by cleaving Malt1ubiquitin chains[J].J Immunol,2009,182(12):7718-7728.
[47]Lobry C,Lopez T,Isra3l A,et al.Negative feedback loop in T cell activation through Ikappa B kinase-induced phosphorylation and degradation of Bcl10[J].Proc Natl Acad Sci U S A,2007,104(3):908-913.
[48]Yang-Yen HF.Mcl-1:A highly regulated cell death and survival controller[J].J Biomed Sci,2006,13(2):201-204.
[49]Warboys CM,de Luca A,Amini N,et al.Disturbed flow promotes endothelial senescence via a p53-dependent pathway[J].Arterioscler Thromb Vasc Biol,2014,34(5):985-995.
[50]Wójcik C.Regulation of apoptosis by the ubiquitin and proteasome pathway[J].J Cell Mol Med,2002,6(1):25-48.
[51]Versari D,Herrmann J,G9ssl M,et al.Dysregulation of the ubiquitin-proteasome system in human carotid atheroscler-osis[J].Arterioscler Thromb Vasc Biol,2006,26(9):2132-2139.
[52]Marfella R,Di Filippo C,Laieta MT,et al.Effects of ubiquitinproteasome system deregulation on the vascular senescence and atherosclerosis process in elderly patients[J].J Gerontol A Biol Sci Med Sci,2008,63(2):200-203.
[2]Li J,Horak KM,Su H,et al.Enhancement of proteasomal function protects against cardiac proteinopathy and ischemia/reperfusion injury in mice[J].J Clin Invest,2011,121(9):3689-3700.
[3]Razeghi P,Baskin KK,Sharma S,et al.Atrophy,hypertrophy,and hypoxemia induce transcriptional regulators of the ubiquitin proteasome system in the rat heart[J].Biochem Biophys Res Commun,2006,342(2):361-364.
[4]Chen Q,Liu JB,Horak KM,et al.Intrasarcoplasmic amyloidosis impairs proteolytic function of proteasomes in cardiomyocytes by compromising substrate uptake[J].Circ Res,2005,97(10):1018-1026.
[5]Wang X,Pattison JS,Su H.Posttranslational modification and quality control[J].Circ Res,2013,112(2):367-381.
[6]Willis MS,Rojas M,Li L,et al.Muscle ring finger 1 mediates cardiac atrophy in vivo[J].Am J Physiol Heart Circ Physiol,2009,296(4):H997-1006.
[7]Powell SR,Herrmann J,Lerman A.The ubiquitin-proteasome system and cardiovascular disease[J].Prog Mol Biol Transl Sci,2012,109:295-346.
[8]Wang X,Terpstra EJ.Ubiquitin receptors and protein quality control[J].J Mol Cell Cardiol,2013,55:73-84.
[9]Powell SR.The ubiquitin-proteasome system in cardiac physiology and pathology[J].Am J Physiol Heart Circ Physiol,2006,291(1):H1-19.
[10]Herrmann J,Lerman LO,Lerman A.Ubiquitin and ubiquitin-like proteins in protein regulation[J].Circ Res,2007,100(9):1276-1291.
[11]Powers ET,Balch WE.Diversity in the origins of proteostasis networks-adriver for protein function in evolution[J].Nat Rev Mol Cell Biol,2013,14(4):237-248.
[12]Calamini B,Morimoto RI.Protein homeostasis as a therapeutic target for diseases of protein conformation[J].Curr Top Med Chem,2012,12(22):2623-2640.
[13]Park C,Cuervo AM.Selective autophagy Talking with the UPS[J].Cell Biochem Biophys,2013,67(1):3-13.
[14]Su H,Wang X.The ubiquitin-proteasome system in cardiac proteinopathy:A quality control perspective[J].Cardiovasc Res,2010,85(2):253-262.
[15]Bhuiyan MS,Pattison JS,Osinska H,et al.Ehanced autophagy ameliorates cardiac proteinopathy[J].J Clin Invest,2013,123(12):5284-5297.
[16]Drews O,Wildgruber R,Zong C,et al.Mammalian proteasome subpopulations with distinct molecular compositions and proteolytic activities[J].Mol Cell Proteomics,2007,6(11):2021-2031.
[17]Bedford L,Lowe J,Dick LR,et al.Ubiquitin-like protein conjugation and the ubiquitin-proteasome system as drug targets[J].Nat Rev Drug Discov,2011,10(1):29-46.
[18]Ashrafian H,Mc Kenna WJ,Watkins H.Disease pathways and novel therapeutic targets in hypertrophic cardiomyopathy[J].Circ Res,2011,109(1):86-96.
[19]Willis MS,Bevilacqua A,Pulinilkunnil T,et al.The role of ubiquitin ligases in cardiac disease[J].J Mol Cell Cardiol,2014,6(71):43-53.
[20]Bahrudin U,Morisaki H,Morisaki T,et al.Ubiquitin-proteasome system impairment caused by a missense cardiac myosin-binding protein C mutation and associated with cardiac dysfunction in hypertrophic cardiomyopathy[J].J Mol Biol,2008,384(4):896-907.
[21]Predmore JM,Wang P,Davis F,et al.Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies[J].Circulation,2010,121(8):997-1004.
[22]Galasso G,De Rosa R,Piscione F,et al.Myocardial expression of FOXO3a-Atrogin-1 pathway in human heart failure[J].Eur J Heart Fail,2010,12(12):1290-1296.
[23]Hein S,Amon E,Kostin S,et al.Progression from compensated hypertrophy to failure in the pressure-overloaded human heart:Structural deterioration and compensatory mechanisms[J].Circulation,2003,107(7):984-991.
[24]Weekes J,Morrison K,Mullen A,et al.Hyperubiquitination of proteins in dilated cardiomyopathy[J].Proteomics,2003,3(2):208-216.
[25]Birks EJ,Latif N,Enesa K,et al.Elevated p53 expression is associated with dysregulation of the ubiquitin-proteasome system in dilated cardiomyopathy[J].Cardiovasc Res,2008,79(3):472-480.
[26]Bennett EJ,Shaler TA,Woodman B,et al.Global changes to the ubiquitin system in Huntington's disease[J].Nature,2007,448(7154):704-708.
[27]Clague MJ,UrbéS.Ubiquitin:Same molecule,different degradation pathways[J].Cell,2010,143(5):682-685.
[28]Lee DY,Brown EJ.Ubiquilins in the crosstalk among proteolytic pathways[J].Biol Chem,2012,393(6):441-447.
[29]Kostin S,Pool L,Elssser A,et al.Myocytes die by multiple mechanisms in failing human hearts[J].Circ Res,2003,92(7):715-724.
[30]Kassiotis C,Ballal K,Wellnitz K,et al.Markets of autophagy are downregulated in failing human heart after mechanical unloading[J].Circulation,2009,120(11 Suppl):S191-197.
[31]Liu J,Chen Q,Huang W,et al.Impairment of the ubiquitin-proteasome system in desminopathy mouse hearts[J].FASEB J,2006,20(2):362-364.
[32]Liu J,Tang M,Mestril R,et al.Aberrant protein aggregation is essential for amutant desmin to impair the proteolytic function of the ubiquitin-proteasome system in cardiomyocytes[J].J Mol Cell Cardiol,2006,40(4):451-454.
[33]Tian Z,Zheng H,Li J,et al.Genetically induced moderate inhibition of the proteasome in cardiomyocytes exacerbates myocardial ischemia-reperfusion injury in mice[J].Circ Res,2012,111(5):532-542.
[34]Herrmann J,Wohlert C,Saguner AM,et al.Primary proteasome inhibition results in cardiac dysfunction[J].Eur J Heart Fail,2013,15(6):614-623.
[35]Huber EM,Basler M,Schwab R,et al.Immuno-and constitutive proteasome crystal structures reveal differences in substrate and inhibitor specificity[J].Cell,2012,148(4):727-738.
[36]Takami Y,Nakagami H,Morishita R,et al.Potential role of CYLD(Cylindromatosis)as a deubiquitinating enzyme in vascular cells[J].Am J Pathol,2008,172(3):818-829.
[37]Herrmann J,Lerman LO,Lerman A.On to the road to degradation:Atherosclerosis and the proteasome[J].Cardiovasc Res,2010,85(2):291-302.
[38]Xia T,Dimitropoulou C,Zeng J,et al.Chaperone-dependent E3ligase CHIP ubiquitinates and mediates proteasomal degradation of soluble guanylyl cyclase[J].Am J Physiol Heart Circ Physiol,2007,293(5):H3080-3087.
[39]Jiang G,Li T,Qiu Y,et al.RNA interference for HIF-1alpha inhibits foam cells formation in vitro[J].Eur J Pharmacol,2007,562(3):183-190.
[40]Diebold I,Djordjevic T,Hess J,et al.Rac-1 promotes pulmonary artery smooth muscle cell proliferation by upregulation of plasminogen activator inhibitor-1:Role of NF kappa B-dependent hypoxia-inducible factor-1alpha transcription[J].Thromb Haemost,2008,100(6):1021-1028.
[41]Hermann J,Gulati R,Napoli C,et al.Oxidative stress-related increase in ubiquitination in early coronary atherogenesis[J].FASEB J,2003,17(12):1730-1732.
[42]Pashevin DA,Tumanovska LV,Dosenko VE,et al.Antiatherogenic effect of quercetin is mediated by proteasome inhibition in the aorta and circulating leukocytes[J].Pharmacol Rep,2011,63(4):1009-1018.
[43]Weber C,Zernecke A,Libby P.The multifaceted contributions of leukocyte subsets to atherosclerosis:Lessons from mouse models[J].Nat Rev Immunol,2008,8(10):802-815.
[44]Zhao JF,Ching LC,Huang YC,et al.Molecular mechanism of curcumin on the suppression of cholesterol accumulation in macrophage foam cells and atherosclerosis[J].Mol Nutr Food Res,2012,56(5):691-701.
[45]Wang Z,Guo D,Yang B,et al.Integrated analysis of microarray data of atherosclerotic plaques:Modulation of the ubiquitin-proteasome system[J].PLo S One,2014,9(10):e110288.
[46]Düwel M,Welteke V,Oeckinghaus A,et al.A20 negatively regulates T cell receptor signaling to NF-kappa B by cleaving Malt1ubiquitin chains[J].J Immunol,2009,182(12):7718-7728.
[47]Lobry C,Lopez T,Isra3l A,et al.Negative feedback loop in T cell activation through Ikappa B kinase-induced phosphorylation and degradation of Bcl10[J].Proc Natl Acad Sci U S A,2007,104(3):908-913.
[48]Yang-Yen HF.Mcl-1:A highly regulated cell death and survival controller[J].J Biomed Sci,2006,13(2):201-204.
[49]Warboys CM,de Luca A,Amini N,et al.Disturbed flow promotes endothelial senescence via a p53-dependent pathway[J].Arterioscler Thromb Vasc Biol,2014,34(5):985-995.
[50]Wójcik C.Regulation of apoptosis by the ubiquitin and proteasome pathway[J].J Cell Mol Med,2002,6(1):25-48.
[51]Versari D,Herrmann J,G9ssl M,et al.Dysregulation of the ubiquitin-proteasome system in human carotid atheroscler-osis[J].Arterioscler Thromb Vasc Biol,2006,26(9):2132-2139.
[52]Marfella R,Di Filippo C,Laieta MT,et al.Effects of ubiquitinproteasome system deregulation on the vascular senescence and atherosclerosis process in elderly patients[J].J Gerontol A Biol Sci Med Sci,2008,63(2):200-203.