DOI QR코드

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Salubrinal Alleviates Pressure Overload-Induced Cardiac Hypertrophy by Inhibiting Endoplasmic Reticulum Stress Pathway

  • Rani, Shilpa (School of Life Sciences, Gwangju Institute of Science and Technology (GIST)) ;
  • Sreenivasaiah, Pradeep Kumar (School of Life Sciences, Gwangju Institute of Science and Technology (GIST)) ;
  • Cho, Chunghee (School of Life Sciences, Gwangju Institute of Science and Technology (GIST)) ;
  • Kim, Do Han (School of Life Sciences, Gwangju Institute of Science and Technology (GIST))
  • Received : 2016.10.26
  • Accepted : 2016.12.30
  • Published : 2017.01.31

Abstract

Pathological hypertrophy of the heart is closely associated with endoplasmic reticulum stress (ERS), leading to maladaptations such as myocardial fibrosis, induction of apoptosis, and cardiac dysfunctions. Salubrinal is a known selective inhibitor of protein phosphatase 1 (PP1) complex involving dephosphorylation of phospho-eukaryotic translation initiation factor 2 subunit $(p-eIF2)-{\alpha}$, the key signaling process in the ERS pathway. In this study, the effects of salubrinal were examined on cardiac hypertrophy using the mouse model of transverse aortic constriction (TAC) and cell model of neonatal rat ventricular myocytes (NRVMs). Treatment of TAC-induced mice with salubrinal ($0.5mg{\cdot}kg^{-1}{\cdot}day^{-1}$) alleviated cardiac hypertrophy and tissue fibrosis. Salubrinal also alleviated hypertrophic growth in endothelin 1 (ET1)-treated NRVMs. Therefore, the present results suggest that salubrinal may be a potentially efficacious drug for treating pathological cardiac remodeling.

Keywords

$eIF2{\alpha}$;ER stress;GRP;$TGF-{\beta}$;transverse aortic constriction

Acknowledgement

Supported by : GIST, NRF

References

  1. Annes, J.P., Munger, J.S., and Rifkin, D.B. (2003). Making sense of latent TGFbeta activation. J. Cell Sci. 116, 217-224. https://doi.org/10.1242/jcs.00229
  2. Berenji, K., Drazner, M.H., Rothermel, B.A., and Hill, J.A. (2005). Does load-induced ventricular hypertrophy progress to systolic heart failure? Am. J. Physiol. Heart Circ. Physiol. 289, H8-H16. https://doi.org/10.1152/ajpheart.01303.2004
  3. Boyce, M., Bryant, K.F., Jousse, C., Long, K., Harding, H.P., Scheuner, D., Kaufman, R.J., Ma, D., Coen, D.M., Ron, D., et al. (2005). A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science 307, 935-939. https://doi.org/10.1126/science.1101902
  4. Cnop, M., Ladriere, L., Hekerman, P., Ortis, F., Cardozo, A.K., Dogusan, Z., Flamez, D., Boyce, M., Yuan, J., and Eizirik, D.L. (2007). Selective inhibition of eukaryotic translation initiation factor 2 alpha dephosphorylation potentiates fatty acid-induced endoplasmic reticulum stress and causes pancreatic beta-cell dysfunction and apoptosis. J. Biol. Chem. 282, 3989-3997.
  5. Desmouliere, A., Geinoz, A., Gabbiani, F., and Gabbiani, G. (1993). Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J. Cell Biol. 122, 103-111. https://doi.org/10.1083/jcb.122.1.103
  6. Dickhout, J.G., Carlisle, R.E., and Austin, R.C. (2011). Interrelationship between cardiac hypertrophy, heart failure, and chronic kidney disease: endoplasmic reticulum stress as a mediator of pathogenesis. Circ. Res. 108, 629-642. https://doi.org/10.1161/CIRCRESAHA.110.226803
  7. Ferri, K.F., and Kroemer, G. (2001). Organelle-specific initiation of cell death pathways. Nat. Cell Biol. 3, E255-263. https://doi.org/10.1038/ncb1101-e255
  8. Frey, N., Katus, H.A., Olson, E.N., and Hill, J.A. (2004). Hypertrophy of the heart: a new therapeutic target? Circulation 109, 1580-1589. https://doi.org/10.1161/01.CIR.0000120390.68287.BB
  9. Fu, H.Y., Okada, K., Liao, Y., Tsukamoto, O., Isomura, T., Asai, M., Sawada, T., Okuda, K., Asano, Y., Sanada, S., et al. (2010). Ablation of C/EBP homologous protein attenuates endoplasmic reticulum-mediated apoptosis and cardiac dysfunction induced by pressure overload. Circulation 122, 361-369. https://doi.org/10.1161/CIRCULATIONAHA.109.917914
  10. Gao, B., Zhang, X.Y., Han, R., Zhang, T.T., Chen, C., Qin, Z.H., and Sheng, R. (2013). The endoplasmic reticulum stress inhibitor salubrinal inhibits the activation of autophagy and neuroprotection induced by brain ischemic preconditioning. Acta Pharmacol. Sin. 34, 657-666. https://doi.org/10.1038/aps.2013.34
  11. Groenendyk, J., Sreenivasaiah, P.K., Kim, D.H., Agellon, L.B., and Michalak, M. (2010). Biology of endoplasmic reticulum stress in the heart. Circ. Res. 107, 1185-1197. https://doi.org/10.1161/CIRCRESAHA.110.227033
  12. Hamid, T., Guo, S.Z., Kingery, J.R., Xiang, X., Dawn, B., and Prabhu, S.D. (2011). Cardiomyocyte $NF-{\kappa}B$ p65 promotes adverse remodelling, apoptosis, and endoplasmic reticulum stress in heart failure. Cardiovasc. Res. 89, 129-138. https://doi.org/10.1093/cvr/cvq274
  13. Huang, Y., Zhang, H., Shao, Z., O'Hara, K.A., Kopilas, M.A., Yu, L., Netticadan, T., and Anderson, H.D. (2011). Suppression of endothelin-1-induced cardiac myocyte hypertrophy by PPAR agonists: role of diacylglycerol kinase zeta. Cardiovasc. Res. 90, 267-275. https://doi.org/10.1093/cvr/cvq401
  14. Kaufman, R.J. (1999). Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev. 13, 1211-1233. https://doi.org/10.1101/gad.13.10.1211
  15. Kim, I., Xu, W., and Reed, J.C. (2008). Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat. Rev. Drug Discovery 7, 1013-1030. https://doi.org/10.1038/nrd2755
  16. Kim, D.Y., Kim, H.R., Kim, K., K., Park, J., W., and Lee, B., J. (2015a). NELL2 function in protection of cells against endoplasmic reticulum stress. Mol. Cells 38, 145-150.
  17. Kim, J.O., Song, D.W., Kwon, E.J., Hong, S.E., Song, H.K., Min, C.K., and Kim, D.H. (2015b). miR-185 Plays an anti-hypertrophic role in the heart via multiple targets in the calcium-signaling pathways. PLoS One 10, e0122509. https://doi.org/10.1371/journal.pone.0122509
  18. Kuwahara, F., Kai, H., Tokuda, K., Kai, M., Takeshita, A., Egashira, K., and Imaizumi, T. (2002). Transforming growth factor-beta function blocking prevents myocardial fibrosis and diastolic dysfunction in pressure-overloaded rats. Circulation 106, 130-135. https://doi.org/10.1161/01.CIR.0000020689.12472.E0
  19. Lee, D.Y., Lee, K.S., Lee, H.J., Kim, D.H., Noh, Y.H., Yu, K., Jung, H.Y., Lee, S.H., Lee, J.Y., Youn, Y.C., et al. (2010). Activation of PERK signaling attenuates Abeta-mediated ER stress. PLoS One. 5, e10489. https://doi.org/10.1371/journal.pone.0010489
  20. Lee, J.H., Kwon, E.J., and Kim, D. H. (2013). Calumenin has a role in the alleviation of ER stress in neonatal rat cardiomyocytes. Biochem. Biophys. Res. Commun. 439, 327-332. https://doi.org/10.1016/j.bbrc.2013.08.087
  21. Levy, D., Garrison, R.J., Savage, D.D., Kannel, W.B., and Castelli, W.P. (1990). Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N. Engl. J. Med. 322, 1561-1566. https://doi.org/10.1056/NEJM199005313222203
  22. Li, R.J., He, K.L., Li, X., Wang, L.L., Liu, C.L., and He, Y.Y. (2015). Salubrinal protects cardiomyocytes against apoptosis in a rat myocardial infarction model via suppressing the dephosphorylation of eukaryotic translation initiation factor $2{\alpha}$. Mol. Med Rep. 12, 1043-1049. https://doi.org/10.3892/mmr.2015.3508
  23. Liu, C.L., Li, X., Hu, G.L., Li, R.J., He, Y.Y., Zhong, W., Li, S., He, K.L., and Wang, L.L. (2012). Salubrinal protects against tunicamycin and hypoxia induced cardiomyocyte apoptosis via the PERK-eIF2alpha signaling pathway. Journal of geriatric cardiology : JGC. 9, 258-268. https://doi.org/10.3724/SP.J.1263.2012.02292
  24. Liu, Y., Wang, J., Qi, S.Y., Ru, L.S., Ding, C., Wang, H.J., Zhao, J.S., Li, J.J., Li, A.Y., and Wang, D.M. (2014). Reduced endoplasmic reticulum stress might alter the course of heart failure via caspase-12 and JNK pathways. Can. J. Cardiol. 30, 368-375. https://doi.org/10.1016/j.cjca.2013.11.001
  25. Nickson, P., Toth, A., and Erhardt, P. (2007). PUMA is critical for neonatal cardiomyocyte apoptosis induced by endoplasmic reticulum stress. Cardiovasc. Res. 73, 48-56. https://doi.org/10.1016/j.cardiores.2006.10.001
  26. Okada, K., Minamino, T., Tsukamoto, Y., Liao, Y., Tsukamoto, O., Takashima, S., Hirata, A., Fujita, M., Nagamachi, Y., Nakatani, T., et al. (2004). Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis. Circulation 110, 705-712. https://doi.org/10.1161/01.CIR.0000137836.95625.D4
  27. Park, C.S., Cha, H., Kwon, E.J., Sreenivasaiah, P.K., and Kim, D. H. (2012). The chemical chaperone 4-phenylbutyric acid attenuates pressure-overload cardiac hypertrophy by alleviating endoplasmic reticulum stress. Biochem. Biophys. Res. Commun. 421, 578-584. https://doi.org/10.1016/j.bbrc.2012.04.048
  28. Ron, D., and Walter, P. (2007). Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 8, 519-529. https://doi.org/10.1038/nrm2199
  29. Rosenkranz, S., Flesch, M., Amann, K., Haeuseler, C., Kilter, H., Seeland, U., Schluter, K.D., and Bohm, M. (2002). Alterations of beta-adrenergic signaling and cardiac hypertrophy in transgenic mice overexpressing TGF-beta(1). Am. J. Physiol. Heart Circ. Physiol. 283, H1253-1262. https://doi.org/10.1152/ajpheart.00578.2001
  30. Szegezdi, E., Macdonald, D.C., Ni Chonghaile, T., Gupta, S., and Samali, A. (2009). Bcl-2 family on guard at the ER. Am. J. Physiol. Cell Physiol. 296, C941-953. https://doi.org/10.1152/ajpcell.00612.2008
  31. Teng, Y., Gao, M., Wang, J., Kong, Q., Hua, H., Luo, T., and Jiang, Y. (2014). Inhibition of eIF2alpha dephosphorylation enhances TRAIL-induced apoptosis in hepatoma cells. Cell Death Dis. 5, e1060. https://doi.org/10.1038/cddis.2014.24
  32. Younce, C.W., and Kolattukudy, P.E. (2010). MCP-1 causes cardiomyoblast death via autophagy resulting from ER stress caused by oxidative stress generated by inducing a novel zinc-finger protein, MCPIP. Biochem. J. 426, 43-53. https://doi.org/10.1042/BJ20090976
  33. Zhang, P., Hamamura, K., Jiang, C., Zhao, L., and Yokota, H. (2012). Salubrinal promotes healing of surgical wounds in rat femurs. J. Bone Miner. Metab. 30, 568-579. https://doi.org/10.1007/s00774-012-0359-z

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