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1 Addiction processes were able to increase HSP-27 expression and phosphorylation, which has cardiac protective effects. These proteins protect the heart, probably preventing cTnT degradation via reducing mu-calpain with cTnT interaction.HSP-27 represents a
Javier Navarro-Zaragoza
 + 906 word(s) 906 2020-05-25 04:26:59 |
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nicole Yin
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Martínez-Laorden, E.; Navarro-Zaragoza, J.; Milanés, M.V.; Laorden, M.L.; Almela, P. Heat Shock Protein 27. Encyclopedia. Available online: https://encyclopedia.pub/entry/928 (accessed on 11 July 2025).
Martínez-Laorden E, Navarro-Zaragoza J, Milanés MV, Laorden ML, Almela P. Heat Shock Protein 27. Encyclopedia. Available at: https://encyclopedia.pub/entry/928. Accessed July 11, 2025.
Martínez-Laorden, Elena, Javier Navarro-Zaragoza, María Victoria Milanés, María Luisa Laorden, Pilar Almela. "Heat Shock Protein 27" Encyclopedia, https://encyclopedia.pub/entry/928 (accessed July 11, 2025).
Martínez-Laorden, E., Navarro-Zaragoza, J., Milanés, M.V., Laorden, M.L., & Almela, P. (2020, May 26). Heat Shock Protein 27. In Encyclopedia. https://encyclopedia.pub/entry/928
Martínez-Laorden, Elena, et al. "Heat Shock Protein 27." Encyclopedia. Web. 26 May, 2020.
Heat Shock Protein 27
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This entry is adapted from the peer-reviewed paper 10.3390/ijms21103623

Heat shock proteins (HSP) are induced after different stress situations. Some of these proteins, particularly HSP-27, function as markers to indicate cellular stress or damage and protect the heart during addictive processes. Morphine withdrawal induces an enhancement of sympathetic activity in parallel with an increased HSP-27 expression and phosphorylation, indicating a severe situation of stress. HSP-27 can interact with different intracellular signaling pathways. Propranolol and SL-327 were able to antagonize the activation of hypothalamic-pituitary adrenal (HPA) axis and the phosphorylation of HSP-27 observed during morphine withdrawal.  Therefore, β-adrenergic receptors and the extracellular signal-regulated kinase (ERK) pathway would be involved in HPA axis activity, and consequently, in HSP-27 activation. Finally, selective blockade of corticotrophin releasing factor (CRF)-1 receptor and the genetic deletion of CRF1 receptors antagonize cardiac adaptive changes. These changes are increased NA turnover, HPA axis activation and decreased HSP-27 expression and phosphorylation. This suggests a link between HPA axis and HSP-27. On the other hand, morphine withdrawal increases µ-calpain expression, which in turn degrades cardiac troponin T (cTnT). This fact, together with a co-localization between cTnT and HSP-27, suggests that this chaperone avoids the degradation of cTnT by µ-calpain, correcting the cardiac contractility abnormalities observed during addictive processes. The aim of our research is to review the possible role of HSP-27 in the cardiac changes observed during morphine withdrawal and to understand the mechanisms implicated in its cardiac protective functions.

Heat shock protein 27 morphine withdrawal stress heart

1. Introduction

In humans, HSP-27 is one of the most important low molecular weight HSP. It is constitutively located in almost all cell types and tissues, but mainly expressed in cardiac tissue[1]. HSP-27 post-translational modification is carried out by phosphorylation at three serine residues (Ser 15, Ser 78, and Ser 82). This phosphorylation is mainly carried out by mitogen activated extracellular signals, although other protein kinases such as protein kinase D, in cell lines and pancreas, and protein kinase C, can also phosphorylate HSP-27, primarily in the residue Ser 82[2].

2. Function

The essential proteins involved in the mechanism of cardiac contraction are actin, myosin, and troponins (Tn). In 1954, Huxley and Hanson[3] proposed the “sliding filament theory”, which states that muscle contraction is the result of the relative slippage of myosin filaments (thick filaments) and actin filaments (thin filaments). Tn is activated in the presence of Ca2+ to expose the actin and myosin binding site. Troponin is a complex formed by three proteins (TnT, TnI, and TnC), each one with a specific function: TnC, which is capable of binding Ca2+; TnT, which binds to tropomyosin in muscle fibers maintaining the bond between actin and myosin; and TnI, which binds to actin in thin myofilaments in order to hold the Tn / tropomyosin complex together, inhibiting the binding of actin and myosin filaments[4][5][6]. The N-terminal region of cardiac TnT and the COOH-terminal region of TnI can undergo a proteolysis by μ-calpain[7][8]. An increase in calpain activity has been observed to cause alterations in myocardial contractility in certain cardiac diseases, while the administration of calpain inhibitors improved cardiac function[9][10]. HSP-27 is somehow involved in cardiac contraction, because ischemia and thermal shock induce a translocation of HSP-27 to the bands Z in cardiac tissue[11][12][13]. The stabilization of actin filaments occurs thanks to the different phosphorylation/dephosphorylation processes, which prevent the degradation and depolymerization induced by oxidative damage or thermal shock[14]. This stabilization seems to be an action caused by the non-phosphorylated form, which is responsible for the HSP activity as a molecular chaperone[15][16], and also participates in the solubilization of the aggregates of denatured proteins after stress[17].

Other functions for HSP-27 would be the modulation of the redox state and the inhibition of apoptotic cell death[18][19] which it is suggested to be mediated by the phosphorylated form[19]. The inhibition of cell death occurs through the direct interaction of HSP-27 with members of the apoptotic machinery that lead to the suppression of the activity of the enzyme caspase, one of the main actors responsible for cell death. A wide range of human diseases and the administration of some drugs have been associated with endoplasmic reticulum stress, which can lead to oxidative stress and therefore, can create an increase in reactive oxygen species (ROS). Endoplasmic reticulum damage induces an increased HSP-27 expression, preventing the generation of ROS and caspase-3 activity and avoiding cell death[20]. In addition, HSP-27 overexpression inhibits cytochrome C release and, consequently, the translocation of pro-death molecules to mitochondria[21].

It is important to highlight that HSP-27 is expressed in both constitutive and inducible form in the cardiac tissue, which gives it an important cardioprotective role. This cardioprotective effect has been extensively studied in animal models. In those studies, it was observed an increase in cell survival against lethal damage caused by cardiac ischemia in mice that overexpress HSP, compared to those that do not overexpress the protein[22]. It has been suggested that HSP-27 contributes to the maintenance of membrane integrity in different types of stress[23] [29], protecting the heart through its functions as chaperone, facilitating the reconstitution of the cytoskeleton after stress. HSP-27 also works as an inducer of antioxidant mechanisms, since the production of free radicals is involved in the generation of myocardial lesions[24][25][26]. Thus, HSP-27 is considered as a potential target for the treatment of myocardial ischemia[6].

In conclusion, HSP-27 increased levels in different tissues suggest a protective role against different type of stress that cause cellular damage. HSP-27 could be considered as adaptive response proteins which enhance survival.

References

  1. K Kato; H Shinohara; S Goto; Y Inaguma; R Morishita; T Asano; Copurification of small heat shock protein with alpha B crystallin from human skeletal muscle.. Journal of Biological Chemistry 1992, 267, 7718–7725.
  2. S Lindquist; E A Craig; The Heat-Shock Proteins. Annual Review of Genetics 1988, 22, 631-677, 10.1146/annurev.ge.22.120188.003215.
  3. Hugh Huxley; Jean Hanson; Changes in the Cross-Striations of Muscle during Contraction and Stretch and their Structural Interpretation. Nature Cell Biology 1954, 173, 973-976, 10.1038/173973a0.
  4. Kobayashi, M.; Debold, E.P.; Turner, M.A.; Kobayashi, T. Cardiac muscle activation blunted by a mutation to the regulatory component, troponin T. J. Biol. Chem. 2013, 288, 26335–26349.
  5. Communal, C.; Sumandea, M.; de Tombe, P.; Narula, J.; Solaro, R.J.; Hajjar, R.J. Functional consequences of caspase activation in cardiac myocytes. Proc. Natl. Acad. Sci. USA 2002, 99, 6252–6256.
  6. Zhang, Z.; Biesiadecki, B.J.; Jin, J. Selective deletion of the NH2-terminal variable region of cardiac troponin T in ischemia reperfusion by myofibril-associated mu-calpain cleavage. Biochemistry 2006, 45, 11681–11694.
  7. McDonough, J.L.; Arrell, D.K.; Van Eyk, J.E. Troponin I degradation and covalent complex formation accompanies myocardial ischemia/reperfusion injury. Cir. Res. 1999, 84, 9–20.
  8. Di Lisa, F.; De Tullio, R.; Salamino, F.; Barbato, R.; Melloni, E.; Siliprandi, N.; Schiaffino, S.; Pontremoli, S. Specific degradation of troponin T and I by mu-calpain and its modulation by substrate phosphorylation. Biochem. J. 1995, 308, 57–61.
  9. Greyson, C.; Schwartz, G.G.; Lu, L.; Ye, S.; Helmke, S.; Xu, Y.; Ahmad, H. Calpain inhibition attenuates right ventricular contractile dysfunction after acute pressure overload. J. Mol. Cell. Cardiol. 2008, 44, 59–68.
  10. Mani, S.K.; Shiraishi, H.; Balasubramanian, S.; Yamane, K.; Chellaiah, M.; Cooper, G.; Banik, N.; Zile, M.R.; Kuppuswamy, D. In vivo administration of calpeptin attenuates calpain activation and cardiomyocyte loss in pressure-overloaded feline myocardium. Am. J. Physiol. Heart. Circ. Physiol. 2008, 295, 314–326.
  11. Yoshida, K.; Maaieh, M.M.; Shipley, J.B.; Doloresco, M.; Bernardo, N.L.; Qian, Y.Z.; Elliott, G.T.; Kukreja, R.C. Monophosphoryl lipid A induces pharmacologic ‘preconditioning’ in rabbit hearts without concomitant expression of 70-kDa heat shock protein. Mol. Cell. Biochem. 1996, 156, 1–8.
  12. White, M.Y.; Hambly, B.D.; Jeremy, R.W.; Cordwell, S.J. Ischemia-specific phosphorylation and myofilament translocation of heat shock protein 27 precede alpha B-crystallin and occurs independently of reactive oxygen species in rabbit myocardium. J. Mol. Cell. Cardiol. 2006, 40, 761–774.
  13. Lu, X.Y.; Chen, L.; Cai, X.L.; Yang, H.T. Overexpression of heat shock protein 27 protects against ischaemia/reperfusion-induced cardiac dysfunction via stabilization of troponin I and T. Cardiovasc. Res. 2008, 79, 500–508.
  14. L M Valentim; R Rodnight; A B Geyer; A P Horn; A Tavares; Helena Cimarosti; Carlos Alexandre Netto; C G Salbego; Changes in heat shock protein 27 phosphorylation and immunocontent in response to preconditioning to oxygen and glucose deprivation in organotypic hippocampal cultures. Neuroscience 2003, 118, 379-386, 10.1016/s0306-4522(02)00919-3.
  15. Guo, Y.; Ziesch, A.; Hocke, S.; Kampmann, E.; Ochs, S.; De Toni, E.N.; Göke, B.; Gallmeier, E. Overexpression of heat shock protein 27 (HSP-27) increases gemcitabine sensitivity in pancreatic cancer cells through S-phase arrest and apoptosis. J. Cell. Mol. Med. 2015, 1, 340–350.
  16. Cuerrier, C.M.; Chen, Y.-X.; Tremblay, D.; Rayner, K.J.; McNulty, M.; Zhao, X.; Kennedy, C.R.J.; De Belleroche, J.; Pelling, A.E.; O’Brien, E. Chronic over-expression of heat shock protein 27 attenuates atherogenesis and enhances plaque remodeling: A combined histological and mechanical assessment of aortic lesions. PLoS ONE 2013, 8, e55867.
  17. Zhanying Guo; Lyndon F. Cooper; An N-Terminal 33-Amino-Acid-Deletion Variant of hsp25 Retains Oligomerization and Functional Properties. Biochemical and Biophysical Research Communications 2000, 270, 183-189, 10.1006/bbrc.2000.2401.
  18. Parcellier, A.; Schmitt, E.; Brunet, M.; Hammann, A.; Solary, E.; Garrido, C. Small heat shock proteins HSP-27 and alphaB-crystallin: Cytoprotective and oncogenic functions. Antioxid. Redox. Signal. 2005, 7, 404–413.
  19. Bruey, J.-M.; Paul, C.; Fromentin, A.; Hilpert, S.; Arrigo, A.-P.; Solary, E.; Garrido, C. Differential regulation of HSP-27 oligomerization in tumor cells grown in vitro and in vivo. Oncogene 2000, 19, 4855–4863.
  20. Audrey Burban; Ahmad Sharanek; Christiane Guguen-Guillouzo; André Guillouzo; Endoplasmic reticulum stress precedes oxidative stress in antibiotic-induced cholestasis and cytotoxicity in human hepatocytes. Free Radical Biology and Medicine 2018, 115, 166-178, 10.1016/j.freeradbiomed.2017.11.017.
  21. R. Anne Stetler; Yanqin Gao; Armando P. Signore; Guodong Cao; Jun Chen; HSP27: mechanisms of cellular protection against neuronal injury.. Current Molecular Medicine 2009, 9, 863-872, 10.2174/156652409789105561.
  22. Christopher A. Efthymiou; Mihaela M. Mocanu; Jackie De Belleroche; Dominic J. Wells; David S. Latchmann; Derek M. Yellon; Heat shock protein 27 protects the heart against myocardial infarction. Basic Research in Cardiology 2004, 99, 392-394, 10.1007/s00395-004-0483-6.
  23. Ibolya Horváth; Gabriele Multhoff; Alois Sonnleitner; László Vígh; Membrane-associated stress proteins: More than simply chaperones. Biochimica et Biophysica Acta (BBA) - Biomembranes 2008, 1778, 1653-1664, 10.1016/j.bbamem.2008.02.012.
  24. Bolli, R. Myocardial ‘stunning’ in man. Circulation 1992, 86, 1671–1691.
  25. Lochner, A.; Marais, E.; Genade, S.; Huisamen, B.; Dutoit, E.F.; Moolman, J.A. Protection of the ischaemic heart: Investigations into the phenomenon of ischaemic preconditioning. Cardiovasc. J. Afr. 2009, 20, 43–51.
  26. Hao, X.; Zhang, S.; Timakov, B.; Zhang, P. The HSP-27 gene is not required for Drosophila development but its activity is associated with starvation resistance. Cell Stress Chaperones 2007, 12, 364–372.
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Subjects: Biochemistry & Molecular Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Elena Martínez-Laorden
,
Javier Navarro-Zaragoza
,
María Victoria Milanés
,
María Luisa Laorden
,
Pilar Almela
View Times: 694
Revisions: 2 times (View History)
Update Date: 02 Nov 2020
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