Full Text:   <1552>

CLC number: R54

On-line Access: 2010-08-02

Received: 2010-06-13

Revision Accepted: 2010-07-05

Crosschecked: 2010-07-08

Cited: 18

Clicked: 4624

Citations:  Bibtex RefMan EndNote GB/T7714

-   Go to

Article info.
1. Reference List
Open peer comments

Journal of Zhejiang University SCIENCE B 2010 Vol.11 No.8 P.608-617


Heat shock protein 90 protects rat mesenchymal stem cells against hypoxia and serum deprivation-induced apoptosis via the PI3K/Akt and ERK1/2 pathways

Author(s):  Feng Gao, Xin-yang Hu, Xiao-jie Xie, Qi-yuan Xu, Ya-ping Wang, Xian-bao Liu, Mei-xiang Xiang, Yong Sun, Jian-an Wang

Affiliation(s):  Department of Cardiology; more

Corresponding email(s):   wang_jian_an@tom.com

Key Words:  Heat shock protein, Apoptosis, Stem cell, Hypoxia, Phosphoinositide-3-kinase/protein kinase B (PI3K/Akt), Extracellular-signal-regulate kinase (ERK)

Feng Gao, Xin-yang Hu, Xiao-jie Xie, Qi-yuan Xu, Ya-ping Wang, Xian-bao Liu, Mei-xiang Xiang, Yong Sun, Jian-an Wang. Heat shock protein 90 protects rat mesenchymal stem cells against hypoxia and serum deprivation-induced apoptosis via the PI3K/Akt and ERK1/2 pathways[J]. Journal of Zhejiang University Science B, 2010, 11(8): 608-617.

@article{title="Heat shock protein 90 protects rat mesenchymal stem cells against hypoxia and serum deprivation-induced apoptosis via the PI3K/Akt and ERK1/2 pathways",
author="Feng Gao, Xin-yang Hu, Xiao-jie Xie, Qi-yuan Xu, Ya-ping Wang, Xian-bao Liu, Mei-xiang Xiang, Yong Sun, Jian-an Wang",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Heat shock protein 90 protects rat mesenchymal stem cells against hypoxia and serum deprivation-induced apoptosis via the PI3K/Akt and ERK1/2 pathways
%A Feng Gao
%A Xin-yang Hu
%A Xiao-jie Xie
%A Qi-yuan Xu
%A Ya-ping Wang
%A Xian-bao Liu
%A Mei-xiang Xiang
%A Yong Sun
%A Jian-an Wang
%J Journal of Zhejiang University SCIENCE B
%V 11
%N 8
%P 608-617
%@ 1673-1581
%D 2010
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B1001007

T1 - Heat shock protein 90 protects rat mesenchymal stem cells against hypoxia and serum deprivation-induced apoptosis via the PI3K/Akt and ERK1/2 pathways
A1 - Feng Gao
A1 - Xin-yang Hu
A1 - Xiao-jie Xie
A1 - Qi-yuan Xu
A1 - Ya-ping Wang
A1 - Xian-bao Liu
A1 - Mei-xiang Xiang
A1 - Yong Sun
A1 - Jian-an Wang
J0 - Journal of Zhejiang University Science B
VL - 11
IS - 8
SP - 608
EP - 617
%@ 1673-1581
Y1 - 2010
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B1001007

Mesenchymal stem cell (MSC) transplantation has shown a therapeutic potential to repair the ischemic and infracted myocardium, but the effects are limited by the apoptosis and loss of donor cells in host cardiac microenvironment. The aim of this study is to explore the cytoprotection of heat shock protein 90 (Hsp90) against hypoxia and serum deprivation-induced apoptosis and the possible mechanisms in rat MSCs. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. apoptosis was assessed by Hoechst 33258 nuclear staining and flow cytometric analysis with annexin V/PI staining. The gene expression of Toll-like receptor-4 (TLR-4) and V-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ErbB2) was detected by real-time polymerase chain reaction (PCR). The protein levels of cleaved caspase-3, Bcl-2, Bcl-xL, Bax, total-ERK, phospho-ERK, total-Akt, phospho-Akt, and Hsp90 were detected by Western blot. The production of nitric oxide was measured by spectrophotometric assay. Hsp90 improves MSC viability and protects MSCs against apoptosis induced by serum deprivation and hypoxia. The protective role of Hsp90 not only elevates Bcl-2/Bax and Bcl-xL/Bax expression and attenuates cleaved caspase-3 expression via down-regulating membrane TLR-4 and ErbB2 receptors and then activating their downstream PI3K/Akt and ERK1/2 pathways, but also enhances the paracrine effect of MSCs. These findings demonstrated a novel and effective treatment strategy against MSC apoptosis in cell transplantation.

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[1]Bishop, S.C., Burlison, J.A., Blagg, B.S., 2007. Hsp90: a novel target for the disruption of multiple signaling cascades. Current Cancer Drug Targets, 7(4):369-388.

[2]Calderwood, S.K., Ciocca, D.R., 2008. Heat shock proteins: stress proteins with Janus-like properties in cancer. International Journal of Hyperthermia, 24(1):31-39.

[3]Chen, T.L., Wang, J.A., Shi, H., Gui, C., Luo, R.H., Xie, X.J., Xiang, M.X., Zhang, X., Cao, J., 2008. Cyclosporin A pre-incubation attenuates hypoxia/reoxygenation-induced apoptosis in mesenchymal stem cells. Scandinavian Journal of Clinical & Laboratory Investigation, 68(7):585-593.

[4]Cheng, A.S., Yau, T.M., 2008. Paracrine effects of cell transplantation: strategies to augment the efficacy of cell therapies. Seminars in Thoracic and Cardiovascular Surgery, 20(2):94-101.

[5]Dai, W., Hale, S.L., Martin, B.J., Kuang, J.Q., Dow, J.S., Wold, L.E., Kloner, R.A., 2005. Allogeneic mesenchymal stem cell transplantation in postinfarcted rat myocardium: short- and long-term effects. Circulation, 112(2):214-223.

[6]Denizot, F., Lang, R., 1986. Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. Journal of Immunological Methods, 89(2):271-277.

[7]Erdmann, F., Jarczowski, F., Weiwad, M., Fischer, G., Edlich, F., 2007. Hsp90-mediated inhibition of FKBP38 regulates apoptosis in neuroblastoma cells. FEBS Letters, 581(29):5709-5714.

[8]Frangogiannis, N.G., Smith, C.W., Entman, M.L., 2002. The inflammatory response in myocardial infarction. Cardiovascular Research, 53(1):31-47.

[9]Gui, C., Wang, J.A., He, A.N., Chen, T.L., Luo, R.H., Jiang, J., Hu, X.Y., Xie, X.J., 2007. Heregulin protects mesenchymal stem cells from serum deprivation and hypoxia-induced apoptosis. Molecular and Cellular Biochemistry, 305(1-2):171-178.

[10]Hahn, J.Y., Cho, H.J., Kang, H.J., Kim, T.S., Kim, M.H., Chung, J.H., Bae, J.W., Oh, B.H., Park, Y.B., Kim, H.S., 2008. Pre-treatment of mesenchymal stem cells with a combination of growth factors enhances gap junction formation, cytoprotective effect on cardiomyocytes, and therapeutic efficacy for myocardial infarction. Journal of the American College of Cardiology, 51(9):933-943.

[11]Hale, S.L., Dai, W., Dow, J.S., Kloner, R.A., 2008. Mesenchymal stem cell administration at coronary artery reperfusion in the rat by two delivery routes: a quantitative assessment. Life Sciences, 83(13-14):511-515.

[12]Hou, D., Youssef, E.A., Brinton, T.J., Zhang, P., Rogers, P., Price, E.T., Yeung, A.C., Johnstone, B.H., Yock, P.G., March, K.L., 2005. Radiolabeled cell distribution after intramyocardial, intracoronary, and interstitial retrograde coronary venous delivery: implications for current clinical trials. Circulation, 112(9 Suppl. I):150-156.

[13]Hou, J.F., Zhang, H., Yuan, X., Li, J., Wei, Y.J., Hu, S.S., 2008. In vitro effects of low-level laser irradiation for bone marrow mesenchymal stem cells: proliferation, growth factors secretion and myogenic differentiation. Lasers in Surgery and Medicine, 40(10):726-733.

[14]Hu, P., Feng, J., Zhou, T., Wang, J., Jing, B., Yu, M., Hu, M., Zhang, X., Shen, B., Guo, N., 2005. In vivo identification of the interaction site of ErbB2 extracellular domain with its autoinhibitor. Journal of Cellular Physiology, 205(3):335-343.

[15]Hu, X., Yu, S.P., Fraser, J.L., Lu, Z., Ogle, M.E., Wang, J.A., Wei, L., 2008. Transplantation of hypoxia-preconditioned mesenchymal stem cells improves infarcted heart function via enhanced survival of implanted cells and angiogenesis. The Journal of Thoracic and Cardiovascular Surgery, 135(4):799-808.

[16]Jung, D.Y., Lee, H., Jung, B.Y., Ock, J., Lee, M.S., Lee, W.H., Suk, K., 2005. TLR4, but not TLR2, signals autoregulatory apoptosis of cultured microglia: a critical role of IFN-β as a decision maker. The Journal of Immunology, 174(10):6467-6476.

[17]Lasker, M.V., Nair, S.K., 2006. Intracellular TLR signaling: a structural perspective on human disease. The Journal of Immunology, 177(1):11-16.

[18]Lee, M.W., Park, S.C., Chae, H.S., Bach, J.H., Lee, H.J., Lee, S.H., Kang, Y.K., Kim, K.Y., Lee, W.B., Kim, S.S., 2001. The protective role of HSP90 against 3-hydroxy-kynurenine-induced neuronal apoptosis. Biochemical and Biophysical Research Communications, 284(2):261-267.

[19]Li, S., Deng, Y., Feng, J., Ye, W., 2009. Oxidative preconditioning promotes bone marrow mesenchymal stem cells migration and prevents apoptosis. Cell Biology International, 33(3):411-418.

[20]Li, W., Ma, N., Ong, L.L., Nesselmann, C., Klopsch, C., Ladilov, Y., Furlani, D., Piechaczek, C., Moebius, J.M., Lutzow, K., et al., 2007. Bcl-2 engineered MSCs inhibited apoptosis and improved heart function. Stem Cells, 25(8):2118-2127.

[21]Liu, X.B., Jiang, J., Gui, C., Hu, X.Y., Xiang, M.X., Wang, J.A., 2008. Angiopoietin-1 protects mesenchymal stem cells against serum deprivation and hypoxia-induced apoptosis through the PI3K/Akt pathway. Acta Pharmacologica Sinica, 29(7):815-822.

[22]Liu, X.B., Hou, J.F., Shi, L.H., Chen, J.H., Sang, J.L., Hu, S.S., Cong, X.F., Chen, X., 2009a. Lysophosphatidic acid protects mesenchymal stem cells against ischemia-induced apoptosis in vivo. Stem Cells and Development, 18(7):947-954.

[23]Liu, X.B., Wang, J.A., Ogle, M.E., Wei, L., 2009b. Prolyl hydroxylase inhibitor dimethyloxalylglycine enhances mesenchymal stem cell survival. Journal of Cellular Biochemistry, 106(5):903-911.

[24]Makino, S., Fukuda, K., Miyoshi, S., Konishi, F., Kodama, H., Pan, J., Sano, M., Takahashi, T., Hori, S., Abe, H., et al., 1999. Cardiomyocytes can be generated from marrow stromal cells in vitro. Journal of Clinical Investigation, 103(5):697-705.

[25]Mias, C., Trouche, E., Seguelas, M.H., Calcagno, F., Dignat-George, F., Sabatier, F., Piercecchi-Marti, M.D., Daniel, L., Bianchi, P., Calise, D., et al., 2008. Ex vivo pretreatment with melatonin improves survival, proangiogenic/mitogenic activity, and efficiency of mesenchymal stem cells injected into ischemic kidney. Stem Cells, 26(7):1749-1757.

[26]Mosmann, T., 1983. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. Journal of Immunological Methods, 65(1-2):55-63.

[27]Nilapwar, S., Williams, E., Fu, C., Prodromou, C., Pearl, L.H., Williams, M.A., Ladbury, J.E., 2009. Structural-thermodynamic relationships of interactions in the N-terminal ATP-binding domain of Hsp90. Journal of Molecular Biology, 392(4):923-936.

[28]Noiseux, N., Gnecchi, M., Lopez-Ilasaca, M., Zhang, L., Solomon, S.D., Deb, A.D., Zau, V.J., Pratt, R.E., 2006. Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Molecular Therapy, 14(6):840-850.

[29]Orlic, D., Kajstura, J., Chimenti, S., Limana, F., Jakoniuk, I., Quaini, F., Nadal-Ginard, B., Bodine, D.M., Leri, A., Anversa, P., 2001. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proceedings of the National Academy of Sciences, 98(18):10344-10349.

[30]Pasha, Z., Wang, Y., Sheikh, R., Zhang, D., Zhao, T., Ashraf, M., 2008. Preconditioning enhances cell survival and differentiation of stem cells during transplantation in infarcted myocardium. Cardiovascular Research, 77(1):134-142.

[31]Stolzing, A., Scutt, A., 2006. Effect of reduced culture temperature on antioxidant defences of mesenchymal stem cells. Free Radical Biology and Medicine, 41(2):326-338.

[32]Stolzing, A., Sethe, S., Scutt, A.M., 2006. Stressed stem cells: temperature response in aged mesenchymal stem cells. Stem Cells and Development, 15(4):478-487.

[33]Tang, Y.L., Tang, Y., Zhang, Y.C., Qian, K., Shen, L., Phillips, M.I., 2005. Improved graft mesenchymal stem cell survival in ischemic heart with a hypoxia-regulated heme oxygenase-1 vector. Journal of the American College of Cardiology, 46(7):1339-1350.

[34]Tsutsumi, S., Beebe, K., Neckers, L., 2009. Impact of heat-shock protein 90 on cancer metastasis. Future Oncology, 5(5):679-688.

[35]van der Bogt, K.E., Schrepfer, S., Yu, J., Sheikh, A.Y., Hoyt, G., Govaert, J.A., Velotta, J.B., Contag, C.H., Robbins, R.C., Wu, J.C., 2009. Comparison of transplantation of adipose tissue- and bone marrow-derived mesenchymal stem cells in the infarcted heart. Transplantation, 87(5):642-652.

[36]Wang, W., Peng, Y., Wang, Y., Zhao, X., Yuan, Z., 2009. Anti-apoptotic effect of heat shock protein 90 on hypoxia-mediated cardiomyocyte damage is mediated via the phosphatidylinositol 3-kinase/Akt pathway. Clinical and Experimental Pharmacology and Physiology, 36(9):899-903.

[37]Wisel, S., Khan, M., Kuppusamy, M.L., Mohan, I.K., Chacko, S.M., Rivera, B.K., Sun, B.C., Hideg, K., Kuppusamy, P., 2009. Pharmacological preconditioning of mesenchymal stem cells with trimetazidine (1-[2,3,4-trimethoxybenzyl] piperazine) protects hypoxic cells against oxidative stress and enhances recovery of myocardial function in infarcted heart through Bcl-2 expression. Journal of Pharmacology and Experimental Therapeutics, 329(2):543-550.

[38]Zhu, X., Zhao, H., Graveline, A.R., Buys, E.S., Schmidt, U., Bloch, K.D., Rosenzweig, A., Chao, W., 2006. MyD88 and NOS2 are essential for toll-like receptor 4-mediated survival effect in cardiomyocytes. AJP Heart and Circulatory Physiology, 291(4):H1900-H1909.

Open peer comments: Debate/Discuss/Question/Opinion


Please provide your name, email address and a comment

Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - Journal of Zhejiang University-SCIENCE