Heat Shock Protein 60 in Vascular Biology
HSP60 in the Vasculature
Abstract
The response of heat shock proteins (HSPs) to stress-induced stimuli is now well documented and understood. Specific HSPs like HSP70 play an important role in vascular diseases like atherosclerosis and hypertension. However, the involvement of other HSPs in these vascular pathologies has been largely ignored. HSP60 plays a particularly critical role in vascular cell growth, an important component of many vascular pathologies. HSP60 directly induces vascular smooth muscle cell proliferation. The mechanism may involve an HSP60-induced stimulation of the rate of nuclear protein import in the smooth muscle cell. HSP60 expression levels also correlate with the severity of the disease. In conclusion, HSP60 may have an important role to play in vascular diseases like atherosclerosis. HSP60 may be a promising future pharmaceutical target to focus upon in order to deter the pathological effects of disease conditions like hypertension and atherosclerosis.
References
Kültz D. Evolution of the cellular stress proteome: from monophyletic origin to ubiquitous function. J Exp Biol. 2003;206(Pt 18):3119-24. doi: 10.1242/jeb.00549.
Fulda S, Gorman AM, Hori O, Samali A. Cellular stress responses: cell survival and cell death. Int J Cell Biol. 2010;2010:214074. doi: 10.1155/2010/214074.
Craig EA. The heat shock response. CRC Crit Rev Biochem. 1985;18(3):239-80. doi: 10.3109/10409238509085135.
Ritossa F. A new puffing pattern induced by temperature shock and DNP in Drosophila. Experientia. 1962;18:571-3. doi: 10.1007/BF02172188.
Tissières A, Mitchell HK, Tracy UM. Protein synthesis in salivary glands of Drosophila melanogaster: relation to chromosome puffs. J Mol Biol. 1974 Apr 15;84(3):389-98. doi: 10.1016/0022-2836(74)90447-1.
Ashburner M, Bonner JJ. The induction of gene activity in drosophilia by heat shock. Cell. 1979 Jun;17(2):241-54. doi: 10.1016/0092-8674(79)90150-8.
Samali A, Orrenius S. Heat shock proteins: regulators of stress response and apoptosis. Cell Stress Chaperones. 1998 Dec;3(4):228-36. doi: 10.1379/1466-1268(1998)003<0228:hspros>2.3.co;2.
Anckar J, Sistonen L. Regulation of HSF1 function in the heat stress response: implications in aging and disease. Annu Rev Biochem. 2011;80:1089-115. doi: 10.1146/annurev-biochem-060809-095203.
Beere HM. “The stress of dying”: the role of heat shock proteins in the regulation of apoptosis. J Cell Sci. 2004;117(Pt 13):2641-51. doi: 10.1242/jcs.01284.
Radons J. The human HSP70 family of chaperones: where do we stand? Cell Stress Chaperones. 2016;21(3):379-404. doi: 10.1007/s12192-016-0676-6.
Parcellier A, Brunet M, Schmitt E, Col E, Didelot C, Hammann A, et al. HSP27 favors ubiquitination and proteasomal degradation of p27Kip1 and helps S-phase re-entry in stressed cells. FASEB J. 2006 Jun;20(8):1179-81. doi: 10.1096/fj.05-4184fje.
Zhang H, Rajasekaran NS, Orosz A, Xiao X, Rechsteiner M, Benjamin IJ. Selective degradation of aggregate-prone CryAB mutants by HSPB1 is mediated by ubiquitin-proteasome pathways. J Mol Cell Cardiol. 2010;49(6):918-30. doi: 10.1016/j.yjmcc.2010.09.004.
Pearl LH, Prodromou C. Structure, function, and mechanism of the HSP90 molecular chaperone. Adv Protein Chem. 2002;59:157-86. doi: 10.1016/s0065-3233(01)59005-1.
Burrows F, Zhang H, Kamal A. HSP90 activation and cell cycle regulation. Cell Cycle. 2004;3(12):1530-6. doi: 10.4161/cc.3.12.1277.
Ryan MT, Pfanner N. Hsp70 proteins in protein translocation. Adv Protein Chem. 2001;59:223-42. doi: 10.1016/s0065-3233(01)59007-5.
Neupert W, Brunner M. The protein import motor of mitochondria. Nat Rev Mol Cell Biol. 2002;3(8):555-65. doi: 10.1038/nrm878.
Didelot C, Schmitt E, Brunet M, Maingret L, Parcellier A, Garrido C. Heat shock proteins: endogenous modulators of apoptotic cell death. Handb Exp Pharmacol. 2006;172:171-98. doi: 10.1007/3-540-29717-0_8.
Kampinga HH, Hageman J, Vos MJ, Kubota H, Tanguay RM, Bruford EA, et al. Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones. 2009;14(1):105-11. doi: 10.1007/s12192-008-0068-7.
Verma S, Goyal S, Jamal S, Singh A, Grover A. HSP90: Friends, clients and natural foes. Biochimie. 2016;127:227-40. doi: 10.1016/j.biochi.2016.05.018.
Langer T, Rosmus S, Fasold H. Intracellular localization of 90kDa heat shock protein (HSP90alpha) determined by expression of a EGFP-HSP90alpha-fusion protein in unstressed and heat stressed 3T3 cells. Cell Biol Int. 2003;27:47-52. doi: 10.1016/s1065-6995(02)00256-1.
Felts SJ, Owen BA, Nguyen P, Trepel J, Donner DB, Toft DO. The hsp90-related protein TRAP1 is a mitochondrial protein with distinct functional properties. J Biol Chem. 2000 Feb 4;275(5):3305-12. doi: 10.1074/jbc.275.5.3305.
Mazzarella RA, Green M. ERp99, an abundant, conserved glycoprotein of the endoplasmic reticulum, is homologous to the 90-kDa heat shock protein (hsp90) and the 94-kDa glucose regulated protein (GRP94). J Biol Chem. 1987 Jun 25;262(18):8875-83. PMID: 3036833.
Flaherty KM, Deluca-Flaherty C, McKay DB. Three-dimensional structure of the ATPase fragment of a 70K heat-shock cognate protein. Nature. 1990;346(6285):623-8. doi: 10.1016/0021-9797(80)90501-9.
Li J, Buchner J. Structure, function and regulation of the HSP90 machinery. Biomed J. 2012;36(3):106-17. doi: 10.4103/2319-4170.113230.
Hessling M, Richter K, Buchner J. Dissection of the ATP-induced conformational cycle of the molecular chaperone HSP90. Nat Struct Mol Biol. 2009;16(3):287-93. doi: 10.1038/nsmb.1565.
Young JC. Mechanisms of the HSP70 chaperone system. Biochem Cell Biol. 2010;88(2):291-300. doi: 10.1139/o09-175.
Mollapour M, Neckers L. Post-translational modifications of HSP90 and their contributions to chaperone regulation. Biochim Biophys Acta - Mol Cell Res. 2012;1823(3):648-55. doi: 10.1016/j.bbamcr.2011.07.018.
Mattoo RUH, Sharma SK, Priya S, Finka A, Goloubinoff P. HSP110 is a bona fide chaperone using ATP to unfold stable misfolded polypeptides and reciprocally collaborate with HSP70 to solubilize protein aggregates. J Biol Chem. 2013;288(29):21399-411. doi: 10.1074/jbc.M113.479253.
Vos MJ, Carra S, Kanon B, Bosveld F, Klauke K, Sibon OC, et al. Specific protein homeostatic functions of small heat-shock proteins increase lifespan. Aging Cell. 2016;15(2):217-226. doi: 10.1111/acel.12422.
Concannon CG, Gorman AM, Samali A. On the role of HSP27 in regulating apoptosis. Apoptosis. 2003;8(1):61-70. doi: 10.1023/a:1021601103096.
Mymrikov E V, Seit-Nebi AS, Gusev NB. Large potentials of small heat shock proteins. Physiol Rev. 2011;91(4):1123-59. doi: 10.1152/physrev.00023.2010.
Treweek TM, Meehan S, Ecroyd H, Carver JA. Small heat-shock proteins: Important players in regulating cellular proteostasis. Cell Mol Life Sci. 2015;72(3):429-51. doi: 10.1007/s00018-014-1754-5.
Carra S, Rusmini P, Crippa V, Giorgetti E, Boncoraglio A, Cristofani R, et al. Different anti-aggregation and pro-degradative functions of the members of the mammalian sHSP family in neurological disorders. Philos Trans R Soc Lond B Biol Sci. 2013;368(1617):20110409. doi: 10.1098/rstb.2011.0409.
Samali A, Cotter TG. Heat shock proteins increase resistance to apoptosis. Exp Cell Res. 1996;223(1):163-70. doi: 10.1006/excr.1996.0070.
Samali A, Robertson JD, Peterson E, Manero F, van Zeijl L, Paul C, et al. HSP27 protects mitochondria of thermotolerant cells against apoptotic stimuli. Cell Stress Chaperones. 2001;6(1):49-58. doi: 10.1379/1466-1268(2001)006<0049:HPMOTC>2.0.CO;2.
Concannon CG, Orrenius S, Samali A. HSP27 inhibits cytochrome c-mediated caspase activation by sequestering both pro-caspase-3 and cytochrome c. Gene Expr. 2001;9(4-5):195-201. doi: 10.3727/000000001783992605.
Lee GJ, Roseman AM, Saibil HR, Vierling E. A small heat shock protein stably binds heat-denatured model substrates and can maintain a substrate in a folding-competent state. EMBO J. 1997;16(3):659-71. doi: 10.1093/emboj/16.3.659.
Mogk A, Schlieker C, Friedrich KL, Schönfeld HJ, Vierling E, Bukau B. Refolding of substrates bound to small HSPs relies on a disaggregation reaction mediated most efficiently by ClpB/DnaK. J Biol Chem. 2003;278(33):31033-42. doi: 10.1074/jbc.M303587200.
Cashikar AG, Duennwald M, Lindquist SL. A chaperone pathway in protein disaggregation: HSP26 alters the nature of protein aggregates to facilitate reactivation by HSP104. J Biol Chem. 2005;280(25):23869-75. doi: 10.1097/MPG.0b013e3181a15ae8.Screening.
Bryantsev AL, Kurchashova SY, Golyshev SA, Polyakov VY, Wunderink HF, Kanon B, et al. Regulation of stress-induced intracellular sorting and chaperone function of HSP27 (HSPB1) in mammalian cells. Biochem J. 2007;407(3):407-17. doi: 10.1042/BJ20070195.
Lelj-Garolla B, Mauk AG. Self-association and chaperone activity of HSP27 are thermally activated. J Biol Chem. 2006;281:8169-74. doi: 10.1074/jbc.M512553200.
Chernik IS, Panasenko OO, Li Y, Marston SB, Gusev NB. pH-induced changes of the structure of small heat shock proteins with molecular mass 24/27kDa (HSPB1). Biochem Biophys Res Commun. 2004;324:1199-203. doi: 10.1016/j.bbrc.2004.09.176.
Maguire M, Coates ARM, Henderson B. Chaperonin 60 unfolds its secrets of cellular communication. Cell Stress Chaperones. 2002;7(4):317-29. doi: 10.1379/1466-1268(2002)007<0317:CUISOC>2.0.CO;2.
Amberger A, Maczek C, Jürgens G, Michaelis D, Schett G, Trieb K, et al. Co-expression of ICAM-1, VCAM-1, ELAM-1 and HSP60 in human arterial and venous endothelial cells in response to cytokines and oxidized low-density lipoproteins. Cell Stress Chaperones. 1997;2(2):94-103. doi: 10.1379/1466-1268(1997)002<0094:CEOIVE>2.3.CO;2.
Hirono S, Dibrov E, Hurtado C, Kostenuk a, Ducas R, Pierce GN. Chlamydia pneumoniae stimulates proliferation of vascular smooth muscle cells through induction of endogenous heat shock protein 60. Circ Res. 2003;93:710-6. doi: 10.1161/01.RES.0000095720.46043.F2.
Martin J, Langer T, Boteva R, Schramel a, Horwich a L, Hartl FU. Chaperonin-mediated protein folding at the surface of groEL through a “molten globule”-like intermediate. Nature. 1991;352(6330):36-42. doi: 10.1038/352036a0.
Zwickl P, Pfeifer G, Lottspeich F, Kopp F, Dahlmann B, Baumeister W. Electron microscopy and image analysis reveal common principles of organization in two large protein complexes: groEL-Type proteins and proteasomes. J Struct Biol. 1990;103(3):197-203. doi: 10.1016/1047-8477(90)90037-D.
Viitanen P V, Lubben TH, Reed J, Goloubinoff P, O’Keefe DP, Lorimer GH. Chaperonin-facilitated refolding of ribulosebisphosphate carboxylase and ATP hydrolysis by chaperonin 60 (groEL) are K+ dependent. Biochemistry. 1990;29(24):5665-71. doi: 10.1021/bi00476a003.
Langer T, Pfeifer G, Martin J, Baumeister W, Hartl FU. Chaperonin-mediated protein folding: GroES binds to one end of the GroEL cylinder, which accommodates the protein substrate within its central cavity. EMBO J. 1992;11(13):4757-65. doi: 10.1002/j.1460-2075.1992.tb05581.x.
Clare DK, Vasishtan D, Stagg S, Quispe J, Farr GW, Topf M, et al. ATP-triggered conformational changes delineate substrate-binding and -folding mechanics of the GroEL chaperonin. Cell. 2012 Mar 30;149(1):113-23. doi: 10.1016/j.cell.2012.02.047.
Liu D, Han X, Zhang Z, Tse G, Shao Q, Liu T. Role of heat shock proteins in atrial fibrillation: From molecular mechanisms to diagnostic and therapeutic opportunities. Cells 2023:12:151. doi: 10.3390/cells12010151.
Soltys BJ, Gupta RS. Cell surface localization of the 60 kDa heat shock chaperonin protein (HSP60) in mammalian cells. Cell Biol Int. 1997;21(5):315-20. doi: 10.1006/cbir.1997.0144.
Cechetto JD, Soltys BJ, Gupta RS. Localization of mitochondrial 60-kD heat shock chaperonin protein (Hsp60) in pituitary growth hormone secretory granules and pancreatic zymogen granules. J Histochem Cytochem. 2000 Jan;48(1):45-56. doi: 10.1177/002215540004800105.
Chandra D, Choy G, Tang DG. Cytosolic accumulation of HSP60 during apoptosis with or without apparent mitochondrial release: Evidence that its pro-apoptotic or pro-survival functions involve differential interactions with caspase-3. J Biol Chem. 2007;282(43):31289-301. doi: 10.1074/jbc.M702777200.
ian J, Guo X, Liu XM, Liu L, Weng QF, Dong SJ, et al. Extracellular HSP60 induces inflammation through activating and up-regulating TLRs in cardiomyocytes. Cardiovasc Res. 2013;98(3):391-401. doi: 10.1093/cvr/cvt047.
de Graaf R, Kloppenburg G, Kitslaar PJ, Bruggeman CA, Stassen F. Human heat shock protein 60 stimulates vascular smooth muscle cell proliferation through Toll-like receptors 2 and 4. Microbes Infect. 2006 Jun;8(7):1859-65. doi: 10.1016/j.micinf.2006.02.024.
Zhao Y, Zhang C, Wei X, Li P, Cui Y, Qin Y, et al. Heat shock protein 60 stimulates the migration of vascular smooth muscle cells via Toll-like receptor 4 and ERK MAPK activation. Sci Rep. 2015 Oct 19;5:15352. doi: 10.1038/srep15352.
Chahine MN, Deniset J, Dibrov E, Hirono S, Blackwood DP, Austria JA, et al. Oxidized LDL promotes the mitogenic actions of Chlamydia pneumoniae in vascular smooth muscle cells. Cardiovasc Res. 2011;92(3):476-83. doi: 10.1093/cvr/cvr251.
Chahine MN, Dibrov E, Blackwood DP, Pierce GN. Oxidized LDL enhances stretch-induced smooth muscle cell proliferation through alterations in nuclear protein import. Can J Physiol Pharmacol. 2012;90:1559-68. doi: 10.1139/y2012-141 10.1124/pr.108.000620.
Kirchhoff SR, Gupta S, Knowlton AA. Cytosolic heat shock protein 60, apoptosis, and myocardial injury. Circulation. 2002;105(24):2899-904. doi: 10.1161/01.CIR.0000019403.35847.23.
Deniset JF, Pierce GN. Heat shock proteins: mediators of atherosclerotic development. Curr Drug Targets. 2015;16(8):816-26. doi: 10.2174/1389450116666150416115423.
Wick G, Jakic B, Buszko M, Wick MC, Grundtman C. The role of heat shock proteins in atherosclerosis. Nat Rev Cardiol. 2014;11(9):516-29. doi: 10.1038/nrcardio.2014.91.
Zhang Y, Lu S, Alahdal M, Gao H, Shen Y, Pan Y, et al. Novel mutant P277 peptide VP to ameliorate atherogenic side-effects and to preserve anti-diabetic effects in NOD mice. Exp Cell Res. 2018 Oct 15;371(2):399-408. doi: 10.1016/j.yexcr.2018.08.034.
Bernardes de Lima Filho J, Freire L, Nahas EAP, Orsatti FL, Orsatti C. Heat shock protein 60 antibodies are associated with a risk factor for cardiovascular disease in bedridden elderly patients. Front Mol Biosci 2020;7:103. doi: 10.3389/fmolb.2020.00103.
Zonnar S, Saeedy SAG, Nernati F, Motamedi MJ, Raeespour H, Amani J. Decrescent role of recombinant HSP60 anitbody against atherosclerosis in high-cholesterol diet immunized rabbits. Iran J Basic Med Sci 2022;25(1):32-8. doi: 10.22038/IJBMS.2021.56382.12580.
Vila-Casahonda RG, Lozano-Aponte J, Gerrero-Beltran CE. HSP60-derived peptide as an LPS/TLR4 modulator: An in silico approach. Front Cardiovasc Med 2022;9:731376. doi: 10.3389/fcvm.2022.731376.
Steinberg D. Low density lipoprotein oxidation and its pathobiological significance. J Biol Chem. 1997 Aug 22;272(34):20963-6. doi: 10.1074/jbc.272.34.20963.
Kleindienst R, Xu Q, Willeit J, Waldenberger FR, Weimann S, Wick G. Immunology of atherosclerosis. Demonstration of heat shock protein 60 expression and T lymphocytes bearing alpha/beta or gamma/delta receptor in human atherosclerotic lesions. Am J Pathol. 1993 Jun;142(6):1927-37. PMID: 8099471.
Hochleitner BW, Hochleitner EO, Obrist P, Eberl T, Amberger A, Xu Q, et al. Fluid shear stress induces heat shock protein 60 expression in endothelial cells in vitro and in vivo. Arterioscler Thromb Vasc Biol. 2000;20:617-23. doi: 10.1161/01.ATV.20.3.617.
Kanwar RK, Kanwar JR, Wang D, Ormrod DJ, Krissansen GW. Temporal expression of heat shock proteins 60 and 70 at lesion-prone sites during atherogenesis in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 2001;21(12):1991-7. doi: 10.1161/hq1201.100263.
Radojevic N, Vukcevic B, Jovovic A, Vukmirovic F. HSP60, SP110 and TNF-a expression in Chlamydia pneumoniae-positive versus Chlamydia pneumoniae-negative atheroscletotic plaques. Pol J Pathol 2021;72(4):338-45. doi: 10.5114/pjp.2021.114179.
Francis AA, Deniset JF, Austria JA, LaValleé RK, Maddaford GG, Hedley TE, et al. Effects of dietary flaxseed on atherosclerotic plaque regression. Am J Physiol Heart Circ Physiol. 2013 Jun 15;304(12):H1743-51. doi: 10.1152/ajpheart.00606.2012.
Deniset JF, Hedley TE, Hlaváčková M, Chahine MN, Dibrov E, O'Hara K, et al. Heat shock protein 60 involvement in vascular smooth muscle cell proliferation. Cell Signal. 2018 Jul;47:44-51. doi: 10.1016/j.cellsig.2018.03.011.
Wick G, Xu Q. Autoimmunity to heat shock proteins in atherosclerosis. Atherosclerosis. 1997;134:289-9.
Henderson B, Pockley a G. Molecular chaperones and protein-folding catalysts as intercellular signaling regulators in immunity and inflammation. J Leukoc Biol. 2010;88(3):445-62. doi: 10.1189/jlb.1209779.
Henderson B, Graham Pockley A. Proteotoxic stress and circulating cell stress proteins in the cardiovascular diseases. Cell Stress Chaperones. 2012;17(3):303-11. doi: 10.1007/s12192-011-0318-y.
Ohashi K, Burkart V, Flohe S, Kolb H. Cutting Edge: Heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J Immunol. 2000;164(2):558-61. doi: 10.4049/jimmunol.164.2.558.
Kol A, Bourcier T, Lichtman AH, Libby P. Chlamydial and human heat shock protein 60s activate human vascular endothelium, smooth muscle cells, and macrophages. J Clin Invest. 1999;103(4):571-577. doi: 10.1172/JCI5310.
Pockley AG, Wu R, Lemne C, Kiessling R, de Faire U, Frostegard J. Circulating heat shock protein 60 is associated with early cardiovascular disease. Hypertension. 2000;36:303-7. doi: 10.1161/01.ATV.0000038493.65177.94.
Xiao Q, Mandal K, Schett G, Mayr M, Wick G, Oberhollenzer F, et al. Association of serum-soluble heat shock protein 60 with carotid atherosclerosis: clinical significance determined in a follow-up study. Stroke. 2005 Dec;36(12):2571-6. doi: 10.1161/01.STR.0000189632.98944.ab.
Zhang X, He M, Cheng L, Chen Y, Zhou L, Zeng H, et al. Elevated heat shock protein 60 levels are associated with higher risk of coronary heart disease in Chinese. Circulation. 2008 Dec 16;118(25):2687-93. doi: 10.1161/CIRCULATIONAHA.108.781856.
Xu Q, Schett G, Perschinka H, Mayr M, Egger G, Oberhollenzer F, et al. Serum soluble heat shock protein 60 is elevated in subjects with atherosclerosis in a general population. Circulation. 2000 Jul 4;102(1):14-20. doi: 10.1161/01.cir.102.1.14.
Kreutmayer S, Csordas A, Kern J, Maass V, Almanzar G, Offterdinger M, et al. Chlamydia pneumoniae infection acts as an endothelial stressor with the potential to initiate the earliest heat shock protein 60-dependent inflammatory stage of atherosclerosis. Cell Stress Chaperones. 2013;18(3):259-68. doi: 10.1007/s12192-012-0378-7.
Schett G, Xu Q, Amberger A, Van der Zee R, Recheis H, Willeit J, et al. Autoantibodies against heat shock protein 60 mediate endothelial cytotoxicity. J Clin Invest. 1995;96(6):2569-77. doi: 10.1172/JCI118320.
Schett G, Metzler B, Mayr M, Amberger A, Niederwieser D, Gupta RS, et al. Macrophage-lysis mediated by autoantibodies to heat shock protein 65/60. Atherosclerosis. 1997;128(1):27-38. doi: 10.1016/S0021-9150(96)05975-8.
Foteinos G, Afzal AR, Mandal K, Jahangiri M, Xu Q. Anti-heat shock protein 60 autoantibodies induce atherosclerosis in apolipoprotein E-deficient mice via endothelial damage. Circulation. 2005;112(8):1206-13. doi: 10.1161/CIRCULATIONAHA.105.547414.
Grundtman C, Kreutmayer SB, Almanzar G, Wick MC. Heat Shock Protein 60 and immune inflammatory responses in atherosclerosis. Arterioscler Thromb. 2011;31(5):960-8. doi: 10.1161/ATVBAHA.110.217877.
Perschinka H, Mayr M, Millonig G, Mayerl C, van der Zee R, Morrison SG, et al. Cross-reactive B-cell epitopes of microbial and human heat shock protein 60/65 in atherosclerosis. Arterioscler Thromb Vasc Biol. 2003 Jun 1;23(6):1060-5. doi: 10.1161/01.ATV.0000071701.62486.49.
Wick C. Tolerization against atherosclerosis using heat shock protein 60. Cell Stress Chaperones. 2016;21(2):201-11. doi: 10.1007/s12192-015-0659-z.
Andrié RP, Bauriedel G, Braun P, Höpp HW, Nickenig G, Skowasch D. Prevalence of intimal heat shock protein 60 homologues in unstable angina and correlation with anti-heat shock protein antibody titers. Basic Res Cardiol. 2011;106(4):657-65. doi: 10.1007/s00395-011-0171-2.
Xu Q, Luef G, Weimann S, Gupta RS, Wolf H, Wick G. Staining of endothelial cells and macrophages in atherosclerotic lesions with human heat-shock protein-reactive antisera. Arterioscler Thromb. 1993 Dec;13(12):1763-9. doi: 10.1161/01.atv.13.12.1763.
Hoppichler F, Koch T, Dzien A, Gschwandtner G, Lechleitner M. Prognostic value of antibody titre to heat-shock protein 65 on cardiovascular events. Cardiology. 2000;94(4):220-3. doi: 10.1159/000047320.
Almanzar G, Öllinger R, Leuenberger J, Onestingel E, Rantner B, Zehm S, et al. Autoreactive HSP60 epitope-specific T-cells in early human atherosclerotic lesions. J Autoimmun. 2012;39(4):441-50. doi: 10.1016/j.jaut.2012.07.006.
Xu Q, Kleindienst R, Waitz W, Dietrich H, Wick G. Increased expression of heat shock protein 65 coincides with a population of infiltrating T lymphocytes in atherosclerotic lesions of rabbits specifically responding to heat shock protein 65. J Clin Invest. 1993;91(6):2693-702. doi: 10.1172/JCI116508.
de Kleer IM, Kamphuis SM, Rijkers GT, Scholtens L, Gordon G, De Jager W, et al. The spontaneous remission of juvenile idiopathic arthritis is characterized by CD30+ T cells directed to human heat-shock protein 60 capable of producing the regulatory cytokine interleukin-10. Arthritis Rheum. 2003;48(7):2001-10. doi: 10.1002/art.11174.
Wieten L, Broere F, van der Zee R, Koerkamp EK, Wagenaar J, van Eden W. Cell stress induced HSP are targets of regulatory T cells: A role for HSP inducing compounds as anti-inflammatory immuno-modulators? FEBS Lett. 2007;581(19):3716-22. doi: 10.1016/j.febslet.2007.04.082.
Zanin-Zhorov A, Cahalon L, Tal G, Margalit R, Lider O, Cohen IR. Heat shock protein 60 enhances CD4+CD25+ regulatory T cell function via innate TLR2 signaling. J Clin Invest. 2006;116(7):2022-32.
Van Puijvelde GHM, Van Es T, Van Wanrooij EJA, et al. Induction of oral tolerance to HSP60 or an HSP60-peptide activates t cell regulation and reduces atherosclerosis. Arterioscler Thromb Vasc Biol. 2007;27(12):2677-83. doi: 10.1161/ATVBAHA.107.151274.
Zhong Y, Tang H, Wang X, Zeng Q, Liu Y, Zhao XI, et al. Intranasal immunization with heat shock protein 60 induces CD4+ CD25+ GARP+ and type 1 regulatory T cells and inhibits early atherosclerosis. Clin Exp Immunol. 2016;183(3):452-68. doi: 10.1111/cei.12726.
Maron R, Sukhova G, Faria AM, Hoffmann E, Mach F, Libby P, et al. Mucosal administration of heat shock protein-65 decreases atherosclerosis and inflammation in aortic arch of low-density lipoprotein receptor-deficient mice. Circulation. 2002;106(13):1708-15. doi: 10.1161/01.CIR.0000029750.99462.30.
Harats D, Yacov N, Gilburd B, Shoenfeld Y, George J. Oral tolerance with heat shock protein 65 attenuates Mycobacterium tuberculosis-induced and high-fat-diet-driven atherosclerotic lesions. J Am Coll Cardiol. 2002;40(7):1333-8. doi: 10.1016/S0735-1097(02)02135-6.
Klingenberg R, Ketelhuth DFJ, Strodthoff D, Gregori S, Hansson GK. Subcutaneous immunization with heat shock protein-65 reduces atherosclerosis in Apoe -/- mice. Immunobiology. 2012;217(5):540-47. doi: 10.1016/j.imbio.2011.06.006.
Chahine MN, Blackwood DP, Dibrov E, Richard MN, Pierce GN. Oxidized LDL affects smooth muscle cell growth through MAPK-mediated actions on nuclear protein import. J Mol Cell Cardiol. 2009 Mar;46(3):431-41. doi: 10.1016/j.yjmcc.2008.10.009.
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).