The interest of scientists in the effects of mechanical stresses on cells is growing, in order to reproduce and understand cell behaviour in an environment closely reproducing physiological conditions. There have been many studies showing that mechanical stimulations are involved in regulating the proliferation, apoptosis and synthesis of proteins and cell morphology. In this study, we have considered the effects of a 20% stretching mechanical stress on MRC5 lung fibroblast cells in order to verify the role of survival/apoptotic pathways. As a survival pathway, the activation of Akt has been studied in association with pro-apoptotic or anti-apoptotic signals such as the Bax/Bcl-2 ratio and cleavage of caspases 3 and 9. Findings have shown the effects of overstressed cellular stretching to be a balance of a cause-and-effect reaction between survival and apoptosis.

Keywords:
Mechanical stress, Akt, Apoptosis, Caspases, Bax/Bcl-2
1.
Adams, J.M., S. Cory (2007) Bcl-2 regulates apoptosis: mechanism and therapeutic potential. Curr Opin Immunol 19: 488–496.
2.
Adrian, C., E.M. Creagh, S.J. Martin (2002) Caspase cascades in apoptosis; in Los, M., M. Walczak (eds): Caspases – Their Role in Cell Death and Cell Survival. New York, Kluwer Academic/Plenum Publishers, pp 41–51.
3.
Biggs, W.H., J. Meisenhelder, T. Hunter, W.K. Cavanee, K.C. Arden (1999) Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. Proc Natl Acad Sci USA 96: 7421–7426.
4.
Boccafoschi, F., M. Bosetti, S. Gatti, M. Cannas (2007) Dynamic fibroblast cultures: response to mechanical stretching. Cell Adh Migr 1: 124–128.
5.
Brunet, A., A. Bonni, M.J. Zigmond, M.Z. Lin, P. Juo, L.S. Hu, M.J. Anderson, K.C. Arden, J. Blenis, M.E. Greenberg (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96: 857–868.
6.
Danciu, T.E., E. Gagari, R.M. Adam, P.D. Damoulis, M.R. Freeman (2004) Mechanical strain delivers anti-apoptotic and proliferative signals to gingival fibroblasts. J Dent Res 83: 596–601.
7.
Franke, T.F., D.R. Kaplan, L.C. Cantley, A. Toker (1997) Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-biphosphate. Science 275: 665–668.
8.
Graf, R., M. Freyberg, D. Kaiser, P. Friedl (2002) Mechanosensitive induction of apoptosis in fibroblasts is regulated by thrombospondin-1 and integrin associated protein (CD47). Apoptosis 7: 493–498.
9.
Hao, Y., C. Xu, S. Sun, F.C. Zhang (2009) Cyclic stretching force induces apoptosis in human periodontal ligament cells via caspase-9. Arch Oral Biol 54: 864–870.
10.
Ingber, D.E. (2006) Mechanical control of tissue morphogenesis during embryological development. Int J Dev Biol 50: 255–266.
11.
Kadohama, T., K. Nishimura, Y. Hoshino, T. Sasajima, B.E. Sumpio (2007) Effects of different types of fluid shear stress on endothelial cell proliferation and survival. J Cell Physiol 212: 244–251.
12.
Kim, D., J. Chung (2002) Akt: versatile mediator of cell survival and beyond. J Biochem Mol Biol 35: 106–115.
13.
Krajewski, S., M. Krajewska, L.M. Ellerby, K. Welsh, Z. Xie, Q.L. Deveraux, G.S. Salvesen, D.E. Bredesen, R.E. Rosenthal, G. Fiskum, J.C. Reed (1999) Release of caspase-9 from mitochondria during neuronal apoptosis and cerebral ischemia. Proc Natl Acad Sci USA 96: 5752–5757.
14.
Liao, X.D., X.H. Wang, H.J. Jin, L.Y. Chen, Q. Chen (2004) Mechanical stretching induces mitochondria-dependent apoptosis in neonatal rat cardiomyocytes and G2/M accumulation in cardiac fibroblasts. Cell Res 14: 16–26.
15.
Liu, J., J. Liu, J. Mao, X. Yuan, Z. Lin, Y. Li (2009) Caspase-3-mediated cyclic stretch-induced myoblast apoptosis via a Fas/FasL-dependent signal pathway during myogenesis. J Cell Biochem 107: 834–844.
16.
Liu, M., A.K. Tanswell, M. Post (1999) Mechanical force-induced signal transduction in lung cells. Am J Physiol 277: L667–L683.
17.
Nicholson, D.W., N.A. Thornberry (1997). Caspases: killer proteases. Trends Biochem Sci 22: 299–306.
18.
Nomura, M., S. Shimizu, T. Ito, M. Narita, H. Matsuda, Y. Tsujimoto (1999) Apoptotic cytosol facilitates Bax translocation to mitochondria that involves cytosolic factor regulated by Bcl-2. Cancer Res 59: 5542–5548.
19.
Nunez, G., M.A. Benedict, Y. Hu, N. Inohara (1998) Caspases: the proteases of the apoptotic pathway. Oncogene 17: 3237–3245.
20.
Pop, C., G.S. Salvesen (2009) Human caspases: activation, specificity and regulation. J Biol Chem 284: 21777–21781.
21.
Raisova, M., A.M. Hossini, J. Eberle, C. Riebeling, T. Wieder, I. Sturm, P.T. Daniel, C.E. Orfanos, C.C. Geilen (2001) The Bax/Bcl-2 ratio determines the susceptibility of human melanoma cells to CD95/Fas-mediated apoptosis. J Invest Dermatol 117: 333–340.
22.
Salakou, S., D. Kardamakis, A.C. Tsamandas, V. Zolota, E. Apostolakis, V. Tzelepi, P. Papathanasopoulos, D.S. Bonikos, T. Papapetropoulos, T. Petsas, D. Dougenis (2007) Increased Bax/Bcl-2 ratio up-regulates caspase-3 and increases apoptosis in the thymus of patients with myasthenia gravis. In Vivo 21: 123–132.
23.
Salvesen, G.S., V.M. Dixit (1997) Caspases: intracellular signaling by proteolysis. Cell 91: 443–446.
24.
Silver, F.H., L.M. Siperko (2003) Mechanosensing and mechanochemical transduction: how is mechanical energy sensed and converted into chemical energy in an extracellular matrix? Crit Rev Biomed Eng 31: 255–331.
25.
Stennicke, H.R., G.S. Salvesen (1998) Properties of caspases. Biochim Biophys Acta 1387: 17–31.
26.
Strasser, A., L. O’Connor, M. Dixit (2000) Apoptosis signaling. Annu Rev Biochem 69: 217–245.
27.
Tang, D., V.J. Kidd (1998) Cleavage of DFF-45/ICAD by multiple caspases is essential for its function during apoptosis. J Biol Chem 273: 28549–28552.
28.
Vogel, V., M.P. Sheetz (2009) Cell fate regulation by coupling mechanical cycles to biomechanical signaling pathways. Curr Opin Cell Biol 21: 38–46.
29.
Yano, S., M. Komine, M. Fujimoto, H. Okochi, K. Tamaki (2006). Activation of Akt by mechanical stretching in human epidermal keratinocytes. Exp Dermatol 15: 356–361.
30.
Yin, X.M., Z.N. Oltvai, S.J. Korsmeyer (1994) BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature 369: 321–332.
© 2010 S. Karger AG, Basel
2010
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.