蛋白翻译后SUMO化修饰在动脉粥样硬化中的作用与机制
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摘要
动脉粥样硬化是过程复杂的慢性炎症性疾病,涉及内皮激活、内皮功能障碍和局部炎症反应等多个关键病理步骤.小分子类泛素修饰因子(small ubiquitin-like modifier,SUMO)化修饰是真核细胞中常见的较新发现的蛋白翻译后修饰,参与多种细胞进程生物学事件,如DNA的转录活性细胞增殖分化、蛋白质的稳定性和定位细胞凋亡以及细胞信号转导等.近期研究发现, SUMO化在动脉粥样硬化发生发展的多个环节中起到重要的调控作用.针对动脉粥样硬化上述几个过程中涉及的蛋白翻译后SUMO化修饰对病程发展的调控作用及其机制的研究现状作一综述.
Atherosclerosis is a complex chronic inflammatory disease involving multiple key pathological steps such as endothelial activation, endothelial dysfunction, and local inflammatory response. SUMOylation is a newly discovered post-translational modification in eukaryotic cells and is involved in a variety of cellular biological events such as cell proliferation and di?erentiation, apoptosis and cell signaling. Recent studies have found that SUMOylation is closely related to the development of atherosclerosis. This paper reviews the research status of the post-translational SUMOylation involved in the process of atherosclerosis and its mechanism.
Atherosclerosis is a complex chronic inflammatory disease involving multiple key pathological steps such as endothelial activation, endothelial dysfunction, and local inflammatory response. SUMOylation is a newly discovered post-translational modification in eukaryotic cells and is involved in a variety of cellular biological events such as cell proliferation and di?erentiation, apoptosis and cell signaling. Recent studies have found that SUMOylation is closely related to the development of atherosclerosis. This paper reviews the research status of the post-translational SUMOylation involved in the process of atherosclerosis and its mechanism.
引文
[1]Benjamin E J,Virani S S.Heart disease and stroke statistics-2018 update:a report from the American Heart Association[J].Circulation,2018,135(10):391-414.
[2] Libby P, Lichtman A H, Hansson G K. Immune effector mechanisms implicated in atherosclerosis:from mice to humans[J]. Immunity, 2013, 38(6):1092-1104.
[3] Yin Y, Pastrana J L, Li X, et al. Inflammasomes:sensors of metabolic stresses for vascular inflammation[J]. Front Biosci(Landmark Ed), 2013, 18:638-649.
[4] Ross R. Atherosclerosis:an inflammatory disease[J]. N Engl J Med, 1999, 340(2):115-126.
[5] Rosenfeld M E. Inflammation and atherosclerosis:direct versus indirect mechanisms[J]. Curr Opin Pharmacol, 2013, 13(2):154-160.
[6] Sihag S, Cresci S, Li A Y, et al. PGC-1alpha and ERRalpha target gene downregulation is a signature of the failing human heart[J]. J Mol Cell Cardiol, 2009, 46(2):201-212.
[7] Pandey D, Chen F, Patel A, et al. SUMO1 negatively regulates reactive oxygen species production from NADPH oxidases[J]. Arterioscler Thromb Vasc Biol, 2011, 31(7):1634-1642.
[8] Woo C H, Abe J. SUMO:a post-translational modification with therapeutic potential?[J].Curr Opin Pharmacol, 2010, 10(2):146-155.
[9] Gimbrone M A, Garcia-Cardena G. Vascular endothelium, hemodynamics, and the pathobiology of atherosclerosis[J]. Cardiovascular Pathology, 2013, 22(1):9-15.
[10] Libby P, Ridker P M, Hansson G K. Progress and challenges in translating the biology of atherosclerosis[J]. Nature, 2011, 473(7347):317-325.
[11] Libby P, Ridker P M, Hansson G K. Inflammation in atherosclerosis:from pathophysiology to practice[J]. J Am Coll Cardiol, 2009, 54(23):2129-2138.
[12] Liao J K. Linking endothelial dysfunction with endothelial cell activation[J]. J Clin Invest,2013, 123(2):540-541.
[13] Gimbrone M J, Garcia-Cardena G. Endothelial cell dysfunction and the pathobiology of atherosclerosis[J]. Circ Res, 2016, 118(4):620-636.
[14] Chang E, Abe J. Kinase-SUMO networks in diabetes-mediated cardiovascular disease[J].Metabolism, 2016, 65(5):623-633.
[15] Hay R T. Decoding the SUMO signal[J]. Biochem Soc Trans, 2013, 41:463-473.
[16] Bailey D, O’Hare P. Characterization of the localization and proteolytic activity of the SUMO-specific protease, SENP1[J]. J Biol Chem, 2004, 279(1):692-703.
[17] Sharma P, Yamada S, Lualdi M, et al. Senp1 is essential for desumoylating Sumo1-modified proteins but dispensable for Sumo2 and Sumo3 deconjugation in the mouse embryo[J]. Cell Rep, 2013, 3(5):1640-1650.
[18] Malek A M, Alper S L, Izumo S. Hemodynamic shear stress and its role in atherosclerosis[J]. JAMA, 1999, 282(21):2035-2042.
[19] Nagel T, Resnick N, Dewey C F, Jr, et al. Vascular endothelial cells respond to spatial gradients in fluid shear stress by enhanced activation of transcription factors[J]. Arterioscler Thromb Vasc Biol, 1999, 19:1825-1834.
[20] Urbich C, Stein M, Reisinger K, et al. Fluid shear stress-induced transcriptional activation of the vascular endothelial growth factor receptor-2 gene requires Sp1-dependent DNA binding[J]. FEBS Lett, 2003, 535:87-93.
[21] Chiu J J, Chien S. Effects of disturbed flow on vascular endothelium:pathophysiological basis and clinical perspectives[J]. Physiol Rev, 2011, 91(1):327-387.
[22] Heo K S, Chang E, Le N T, et al. De-SUMOylation enzyme of sentrin/SUMO-specific protease2 regulates disturbed flow-induced SUMOylation of ERK5 and p53 that leads to endothelial dysfunction and atherosclerosis[J]. Circ Res, 2013, 112(6):911-923.
[23] Heo K S, Lee H, Nigro P, et al. PKCzeta mediates disturbed flow-induced endothelial apoptosis via p53 SUMOylation[J]. J Cell Biol, 2011, 193(5):867-884.
[24] Heo K S, Le N T, Cushman H J, et al. Disturbed flow-activated p90RSK kinase accelerates atherosclerosis by inhibiting SENP2 function[J]. J Clin Invest, 2015, 125(3):1299-1310.
[25] Woo C H, Shishido T, McClain C, et al. Extracellular signal-regulated kinase 5 SUMOylation antagonizes shear stress-induced anti-inflammatory response and endothelial nitric oxide synthase expression in endothelial cells[J]. Circ Res, 2008, 102(5):538-545.
[26] Nichols T C, Fischer T H, Deliargyris E N, et al. Role of nuclear factor-kappa B(NFkappa B)in inflammation, periodontitis, and atherogenesis[J]. Ann Periodontol, 2001, 6(1):20-29.
[27] Wang Y, Wang G Z, Rabinovitch P S, et al. Macrophage mitochondrial oxidative stress promotes atherosclerosis and nuclear factor-κB-mediated inflammation in macrophages[J]. Circ Res, 2014, 114(3):421-433.
[28] Liu B, Mink S, Wong K A, et al. PIAS1 selectively inhibits interferon-inducible genes and is important in innate immunity[J]. Nat Immunol, 2004, 5:891-898.
[29] Liu B, Yang R, Wong K A, et al. Negative regulation of NF-κB signaling by PIAS1[J]. Mol Cell Biol, 2005, 25:1113-1123.
[30] Lawrence T, Bebien M, Liu G Y, et al. IKKαlimits macrophage NF-κB activation and contributes to the resolution of inflammation[J]. Nature, 2005, 434:1138-1143.
[31] Hsueh W A, Jackson S, Law R E. Control of vascular cell proliferation and migration by PPAR-gamma:a new approach to the macrovascular complications of diabetes[J]. Diabetes Care, 2001, 24:392-397.
[32] Law R E, Goetze S, Xi X P, et al. Expression and function of PPARgamma in rat and human vascular smooth muscle cells[J]. Circulation, 2000, 101:1311-1318.
[33] Zhang Y, Yang X, Bian F, et al. TNF-αpromotes early atherosclerosis by increasing transcytosis of LDL across endothelial cells:crosstalk between NF-κB and PPAR-γ[J]. J Mol Cell Cardiol, 2014, 72:85-94.
[34] Pascual G, Fong A L, Ogawa S, et al. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma[J]. Nature, 2005, 437(7059):759-763.
[35] Im S S, Osborne T F. Liver x receptors in atherosclerosis and inflammation[J]. Circ Res, 2011,108(8):996-1001.
[36] Calkin A C, Tontonoz P. Liver x receptor signaling pathways and atherosclerosis[J]. Arterioscler Thromb Vasc Biol, 2010, 30:1513-1518.
[37] Morello F, Saglio E, Noghero A, et al. LXR-activating oxysterols induce the expression of inflammatory markers in endothelial cells through LXR-independent mechanisms[J]. Atherosclerosis, 2009, 207:38-44.
[38] Bi X, Song J, Gao J, et al. Activation of liver X receptor attenuates lysophosphatidylcholineinduced IL-8 expression in endothelial cells via the NF-κB pathway and SUMOylation[J]. J Cell Mol Med, 2016, 20(12):2249-2258.
[39] Moore K J, Tabas I. Macrophages in the pathogenesis of atherosclerosis[J]. Cell, 2011, 145(3):341-355.
[40] Oishi Y, Manabe I, Tobe K, et al. SUMOylation of Kruppel-like transcription factor 5 acts as a molecular switch in transcriptional programs of lipid metabolism involving PPAR-delta[J].Nat Med, 2008, 14(6):656-666.
[41] Makowski L, Brittingham K C, Reynolds J M, et al. The fatty acidbinding protein,aP2, coordinates macrophage cholesterol trafficking and inflammatory activity. Macrophage expression of aP2 impacts peroxisome proliferator-activated receptor gamma and IkappaB kinase activities[J]. J Biol Chem, 2005, 280(13):12888-12895.
[42] Erbay E, Babaev V R, Mayers J R, et al. Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis[J]. Nat Med, 2009, 15(12):1383-1391.
[43] Jiang Z, Fan Q, Zhang Z, et al. SENP1 deficiency promotes ER stress-induced apoptosis by increasing XBP1 SUMOylation[J]. Cell Cycle, 2012, 11(6):1118-1122.
[44] David R. Autophagy:TFEB perfects multitasking[J]. Nature Reviews Molecular Cell Biology,2011, 12(7):404.
[45] Sardiello M, Palmieri M, Di Ronza A, et al. A gene network regulating lysosomal biogenesis and function[J]. Science, 2009, 325(5939):473-477.
[46] Miller A J, Levy C, Davis I J, et al. Sumoylation of MITF and its related family members TFE3 and TFEB[J]. J Biol Chem, 2005, 280(1):146-155.
[47] Pang Q, Xiong J, Hu X L, et al. UFM1 protects macrophages from oxLDL-induced foam cell formation through a liver X receptorαdependent pathway[J]. J Atheroscler Thromb, 2015,22(11):1124-1140.
[48] Liu M W, Roubin G S, King S B. Restenosis after coronary angioplasty. Potential biologic determinants and role of intimal hyperplasia[J]. Circulation, 1989, 79(6):1374-1387.
[49] Phillips J W, Barringhaus K G, Sanders J M, et al. Rosiglitazone reduces the accelerated neointima formation after arterial injury in a mouse injury model of type 2 diabetes[J].Circulation, 2003, 108:1994-1999.
[50] Mangelsdorf D J, Thummel C, Beato M, et al. The nuclear receptor superfamily:the second decade[J]. Cell, 1995, 83(6):835-839.
[51] Sentis S, Le Romancer M, Bianchin C, et al. Sumoylation of the estrogen receptor alpha hinge region regulates its transcriptional activity[J]. Mol Endocrinol, 2005, 19(11):2671-2684.
[52] Kobayashi S, Shibata H, Yokota K, et al. FHL2, UBC9, and PIAS1 are novel estrogen receptor alpha-interacting proteins[J]. Endocr Res, 2004, 30(4):617-621.
[53] Tahk S, Liu B, Chernishof V, et al. Control of specificity and magnitude of NF-kappa B and STAT1-mediated gene activation through PIASy and PIAS1 cooperation[J]. Proc Natl Acad Sci U S A, 2007, 104(28):11643-11648.
[2] Libby P, Lichtman A H, Hansson G K. Immune effector mechanisms implicated in atherosclerosis:from mice to humans[J]. Immunity, 2013, 38(6):1092-1104.
[3] Yin Y, Pastrana J L, Li X, et al. Inflammasomes:sensors of metabolic stresses for vascular inflammation[J]. Front Biosci(Landmark Ed), 2013, 18:638-649.
[4] Ross R. Atherosclerosis:an inflammatory disease[J]. N Engl J Med, 1999, 340(2):115-126.
[5] Rosenfeld M E. Inflammation and atherosclerosis:direct versus indirect mechanisms[J]. Curr Opin Pharmacol, 2013, 13(2):154-160.
[6] Sihag S, Cresci S, Li A Y, et al. PGC-1alpha and ERRalpha target gene downregulation is a signature of the failing human heart[J]. J Mol Cell Cardiol, 2009, 46(2):201-212.
[7] Pandey D, Chen F, Patel A, et al. SUMO1 negatively regulates reactive oxygen species production from NADPH oxidases[J]. Arterioscler Thromb Vasc Biol, 2011, 31(7):1634-1642.
[8] Woo C H, Abe J. SUMO:a post-translational modification with therapeutic potential?[J].Curr Opin Pharmacol, 2010, 10(2):146-155.
[9] Gimbrone M A, Garcia-Cardena G. Vascular endothelium, hemodynamics, and the pathobiology of atherosclerosis[J]. Cardiovascular Pathology, 2013, 22(1):9-15.
[10] Libby P, Ridker P M, Hansson G K. Progress and challenges in translating the biology of atherosclerosis[J]. Nature, 2011, 473(7347):317-325.
[11] Libby P, Ridker P M, Hansson G K. Inflammation in atherosclerosis:from pathophysiology to practice[J]. J Am Coll Cardiol, 2009, 54(23):2129-2138.
[12] Liao J K. Linking endothelial dysfunction with endothelial cell activation[J]. J Clin Invest,2013, 123(2):540-541.
[13] Gimbrone M J, Garcia-Cardena G. Endothelial cell dysfunction and the pathobiology of atherosclerosis[J]. Circ Res, 2016, 118(4):620-636.
[14] Chang E, Abe J. Kinase-SUMO networks in diabetes-mediated cardiovascular disease[J].Metabolism, 2016, 65(5):623-633.
[15] Hay R T. Decoding the SUMO signal[J]. Biochem Soc Trans, 2013, 41:463-473.
[16] Bailey D, O’Hare P. Characterization of the localization and proteolytic activity of the SUMO-specific protease, SENP1[J]. J Biol Chem, 2004, 279(1):692-703.
[17] Sharma P, Yamada S, Lualdi M, et al. Senp1 is essential for desumoylating Sumo1-modified proteins but dispensable for Sumo2 and Sumo3 deconjugation in the mouse embryo[J]. Cell Rep, 2013, 3(5):1640-1650.
[18] Malek A M, Alper S L, Izumo S. Hemodynamic shear stress and its role in atherosclerosis[J]. JAMA, 1999, 282(21):2035-2042.
[19] Nagel T, Resnick N, Dewey C F, Jr, et al. Vascular endothelial cells respond to spatial gradients in fluid shear stress by enhanced activation of transcription factors[J]. Arterioscler Thromb Vasc Biol, 1999, 19:1825-1834.
[20] Urbich C, Stein M, Reisinger K, et al. Fluid shear stress-induced transcriptional activation of the vascular endothelial growth factor receptor-2 gene requires Sp1-dependent DNA binding[J]. FEBS Lett, 2003, 535:87-93.
[21] Chiu J J, Chien S. Effects of disturbed flow on vascular endothelium:pathophysiological basis and clinical perspectives[J]. Physiol Rev, 2011, 91(1):327-387.
[22] Heo K S, Chang E, Le N T, et al. De-SUMOylation enzyme of sentrin/SUMO-specific protease2 regulates disturbed flow-induced SUMOylation of ERK5 and p53 that leads to endothelial dysfunction and atherosclerosis[J]. Circ Res, 2013, 112(6):911-923.
[23] Heo K S, Lee H, Nigro P, et al. PKCzeta mediates disturbed flow-induced endothelial apoptosis via p53 SUMOylation[J]. J Cell Biol, 2011, 193(5):867-884.
[24] Heo K S, Le N T, Cushman H J, et al. Disturbed flow-activated p90RSK kinase accelerates atherosclerosis by inhibiting SENP2 function[J]. J Clin Invest, 2015, 125(3):1299-1310.
[25] Woo C H, Shishido T, McClain C, et al. Extracellular signal-regulated kinase 5 SUMOylation antagonizes shear stress-induced anti-inflammatory response and endothelial nitric oxide synthase expression in endothelial cells[J]. Circ Res, 2008, 102(5):538-545.
[26] Nichols T C, Fischer T H, Deliargyris E N, et al. Role of nuclear factor-kappa B(NFkappa B)in inflammation, periodontitis, and atherogenesis[J]. Ann Periodontol, 2001, 6(1):20-29.
[27] Wang Y, Wang G Z, Rabinovitch P S, et al. Macrophage mitochondrial oxidative stress promotes atherosclerosis and nuclear factor-κB-mediated inflammation in macrophages[J]. Circ Res, 2014, 114(3):421-433.
[28] Liu B, Mink S, Wong K A, et al. PIAS1 selectively inhibits interferon-inducible genes and is important in innate immunity[J]. Nat Immunol, 2004, 5:891-898.
[29] Liu B, Yang R, Wong K A, et al. Negative regulation of NF-κB signaling by PIAS1[J]. Mol Cell Biol, 2005, 25:1113-1123.
[30] Lawrence T, Bebien M, Liu G Y, et al. IKKαlimits macrophage NF-κB activation and contributes to the resolution of inflammation[J]. Nature, 2005, 434:1138-1143.
[31] Hsueh W A, Jackson S, Law R E. Control of vascular cell proliferation and migration by PPAR-gamma:a new approach to the macrovascular complications of diabetes[J]. Diabetes Care, 2001, 24:392-397.
[32] Law R E, Goetze S, Xi X P, et al. Expression and function of PPARgamma in rat and human vascular smooth muscle cells[J]. Circulation, 2000, 101:1311-1318.
[33] Zhang Y, Yang X, Bian F, et al. TNF-αpromotes early atherosclerosis by increasing transcytosis of LDL across endothelial cells:crosstalk between NF-κB and PPAR-γ[J]. J Mol Cell Cardiol, 2014, 72:85-94.
[34] Pascual G, Fong A L, Ogawa S, et al. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma[J]. Nature, 2005, 437(7059):759-763.
[35] Im S S, Osborne T F. Liver x receptors in atherosclerosis and inflammation[J]. Circ Res, 2011,108(8):996-1001.
[36] Calkin A C, Tontonoz P. Liver x receptor signaling pathways and atherosclerosis[J]. Arterioscler Thromb Vasc Biol, 2010, 30:1513-1518.
[37] Morello F, Saglio E, Noghero A, et al. LXR-activating oxysterols induce the expression of inflammatory markers in endothelial cells through LXR-independent mechanisms[J]. Atherosclerosis, 2009, 207:38-44.
[38] Bi X, Song J, Gao J, et al. Activation of liver X receptor attenuates lysophosphatidylcholineinduced IL-8 expression in endothelial cells via the NF-κB pathway and SUMOylation[J]. J Cell Mol Med, 2016, 20(12):2249-2258.
[39] Moore K J, Tabas I. Macrophages in the pathogenesis of atherosclerosis[J]. Cell, 2011, 145(3):341-355.
[40] Oishi Y, Manabe I, Tobe K, et al. SUMOylation of Kruppel-like transcription factor 5 acts as a molecular switch in transcriptional programs of lipid metabolism involving PPAR-delta[J].Nat Med, 2008, 14(6):656-666.
[41] Makowski L, Brittingham K C, Reynolds J M, et al. The fatty acidbinding protein,aP2, coordinates macrophage cholesterol trafficking and inflammatory activity. Macrophage expression of aP2 impacts peroxisome proliferator-activated receptor gamma and IkappaB kinase activities[J]. J Biol Chem, 2005, 280(13):12888-12895.
[42] Erbay E, Babaev V R, Mayers J R, et al. Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis[J]. Nat Med, 2009, 15(12):1383-1391.
[43] Jiang Z, Fan Q, Zhang Z, et al. SENP1 deficiency promotes ER stress-induced apoptosis by increasing XBP1 SUMOylation[J]. Cell Cycle, 2012, 11(6):1118-1122.
[44] David R. Autophagy:TFEB perfects multitasking[J]. Nature Reviews Molecular Cell Biology,2011, 12(7):404.
[45] Sardiello M, Palmieri M, Di Ronza A, et al. A gene network regulating lysosomal biogenesis and function[J]. Science, 2009, 325(5939):473-477.
[46] Miller A J, Levy C, Davis I J, et al. Sumoylation of MITF and its related family members TFE3 and TFEB[J]. J Biol Chem, 2005, 280(1):146-155.
[47] Pang Q, Xiong J, Hu X L, et al. UFM1 protects macrophages from oxLDL-induced foam cell formation through a liver X receptorαdependent pathway[J]. J Atheroscler Thromb, 2015,22(11):1124-1140.
[48] Liu M W, Roubin G S, King S B. Restenosis after coronary angioplasty. Potential biologic determinants and role of intimal hyperplasia[J]. Circulation, 1989, 79(6):1374-1387.
[49] Phillips J W, Barringhaus K G, Sanders J M, et al. Rosiglitazone reduces the accelerated neointima formation after arterial injury in a mouse injury model of type 2 diabetes[J].Circulation, 2003, 108:1994-1999.
[50] Mangelsdorf D J, Thummel C, Beato M, et al. The nuclear receptor superfamily:the second decade[J]. Cell, 1995, 83(6):835-839.
[51] Sentis S, Le Romancer M, Bianchin C, et al. Sumoylation of the estrogen receptor alpha hinge region regulates its transcriptional activity[J]. Mol Endocrinol, 2005, 19(11):2671-2684.
[52] Kobayashi S, Shibata H, Yokota K, et al. FHL2, UBC9, and PIAS1 are novel estrogen receptor alpha-interacting proteins[J]. Endocr Res, 2004, 30(4):617-621.
[53] Tahk S, Liu B, Chernishof V, et al. Control of specificity and magnitude of NF-kappa B and STAT1-mediated gene activation through PIASy and PIAS1 cooperation[J]. Proc Natl Acad Sci U S A, 2007, 104(28):11643-11648.