Salubrinal protects cardiomyocytes against apoptosis in a rat myocardial infarction model via suppressing the dephosphorylation of eukaryotic translation initiation factor 2α

Li,Rui‑Jun; He,Kun‑Lun; Li,Xin; Wang,Li‑Li; Liu,Chun‑Lei; He,Yun‑Yun

doi:10.3892/mmr.2015.3508

Salubrinal protects cardiomyocytes against apoptosis in a rat myocardial infarction model via suppressing the dephosphorylation of eukaryotic translation initiation factor 2α

Authors:
- Rui‑Jun Li
- Kun‑Lun He
- Xin Li
- Li‑Li Wang
- Chun‑Lei Liu
- Yun‑Yun He
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Affiliations: Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, P.R. China, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, P.R. China
Published online on: March 18, 2015 https://doi.org/10.3892/mmr.2015.3508
Pages: 1043-1049
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

The aim of the present study was to examine the role of eIF2α in cardiomyocyte apoptosis and evaluate the cardioprotective role of salubrinal in a rat myocardial infarction (MI) model. Rat left anterior descending coronary arteries were ligated and the classical proteins involved in the endoplasmic reticulum stress (ERS)‑induced apoptotic pathway were analyzed using quantitative polymerase chain reaction and western blot analysis. Salubrinal was administered to the rats and cardiomyocyte apoptosis and infarct size were evaluated by a specific staining method. Compared with the sham surgery group, the rate of cardiomyocyte apoptosis in the MI group was increased with the development of the disease. It was also demonstrated that the mRNA and protein levels of GRP78, caspase‑12, CHOP and the protein expression of p‑eIF2α were increased in the MI group. Furthermore, the results showed that treatment with salubrinal can decrease cardiomyocyte apoptosis and infarct size by increasing eIF2α phosphorylation and decreasing the expression of caspase‑12 and CHOP. The present study suggests that salubrinal protects against ER stress‑induced rat cadiomyocyte apoptosis via suppressing the dephosphorylation of eIF2α in the ERS-associated pathway.

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1	Gajarsa JJ and Kloner R: Left ventricular remodeling in the post-infarction heart: A review of cellular, molecular mechanisms, and therapeutic modalities. Heart Fail Rev. 16:13–21. 2011. View Article : Google Scholar
2	Abbate A, Salloum FN, Vecile E, et al: Anakinra, a recombinant human interleukin-1 receptor antagonist, inhibits apoptosis in experimental acute myocardial infarction. Circulation. 117:2670–2683. 2008. View Article : Google Scholar : PubMed/NCBI
3	Takemura G and Fujiwara H: Role of apoptosis in remodeling after myocardial infarction. Pharmacol Ther. 104:1–16. 2004. View Article : Google Scholar : PubMed/NCBI
4	Schröder M: Endoplasmic reticulum stress responses. Cell Mol Life Sci. 65:862–894. 2008. View Article : Google Scholar
5	Miyazaki Y, Kaikita K, Endo M, et al: C/EBP homologous protein deficiency attenuates myocardial reperfusion injury by inhibiting myocardial apoptosis and inflammation. Arterioscler Thromb Vasc Biol. 31:1124–1132. 2011. View Article : Google Scholar : PubMed/NCBI
6	Xu C, Bailly-Maitre B and Reed JC: Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest. 115:2656–2664. 2005. View Article : Google Scholar : PubMed/NCBI
7	Lee AS: The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress. Methods. 35:373–381. 2005. View Article : Google Scholar : PubMed/NCBI
8	Lin JH, Li H, Yasumura D, et al: IRE1 signaling affects cell fate during the unfolded protein response. Science. 318:944–949. 2007. View Article : Google Scholar : PubMed/NCBI
9	Lai EWS: Diabetes and endoplasmic reticulum stress in pancreatic β-cells: effects on insulin biosynthesis and β-cell apoptosis. Master of Science dissertation. University of Toronto; Toronto, Canada: 2008
10	Ron D: Translational control in the endoplasmic reticulum stress response. J Clin Invest. 110:1383–1388. 2002. View Article : Google Scholar : PubMed/NCBI
11	Mitra A, Basak T, Datta K, Naskar S, Sengupta S and Sarkar S: Role of α-crystallin B as a regulatory switch in modulating cardiomyocyte apoptosis by mitochondria or endoplasmic reticulum during cardiac hypertrophy and myocardial infarction. Cell Death Dis. 4:e5822013. View Article : Google Scholar
12	Boyce M, Bryant KF, Jousse C, et al: A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science. 307:935–939. 2005. View Article : Google Scholar : PubMed/NCBI
13	Wiseman RL and Balch WE: A new pharmacology-drugging stressed folding pathways. Trends Mol Med. 11:347–350. 2005. View Article : Google Scholar : PubMed/NCBI
14	Zhu Y, Fenik P, Zhan G, Sanfillipo-Cohn B, Naidoo N and Veasey SC: Eif-2a protects brainstem motoneurons in a murine model of sleep apnea. J Neurosci. 28:2168–2178. 2008. View Article : Google Scholar : PubMed/NCBI
15	Sokka AL, Putkonen N, Mudo G, et al: Endoplasmic reticulum stress inhibition protects against excitotoxic neuronal injury in the rat brain. J Neurosci. 27:901–908. 2007. View Article : Google Scholar : PubMed/NCBI
16	Liu Y, Wang J, Qi SY, et al: Reduced endoplasmic reticulum stress might alter the course of heart failure via caspase-12 and JNK pathways. Can J Cardiol. 30:368–375. 2014. View Article : Google Scholar : PubMed/NCBI
17	Paschen W: Endoplasmic reticulum: a primary target in various acute disorders and degenerative diseases of the brain. Cell Calcium. 34:365–383. 2003. View Article : Google Scholar : PubMed/NCBI
18	Gasparetto M, Gentry T, Sebti S, et al: Identification of compounds that enhance the anti-lymphoma activity of rituximab using flow cytometric high-content screening. J Immunol Methods. 292:59–71. 2004. View Article : Google Scholar : PubMed/NCBI
19	Katsoulieris E, Mabley JG, Samai M, Green IC and Chatterjee PK: alpha-Linolenic acid protects renal cells against palmitic acid lipotoxicity via inhibition of endoplasmic reticulum stress. Eur J Pharmacol. 623:107–112. 2009. View Article : Google Scholar : PubMed/NCBI
20	Cnop M, Ladriere L, Hekerman P, et al: 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. 2007. View Article : Google Scholar
21	Liu CL, Li X, Hu GL, et al: Salubrinal protects against tunicamycin and hypoxia induced cardiomyocyte apoptosis via the PERK-eIF2α signaling pathway. J Geriatr Cardiol. 9:258–268. 2012.PubMed/NCBI
22	Martindale JJ, Wall JA, Martinez-Longoria DM, et al: Overexpression of mitogen-activated protein kinase kinase 6 in the heart improves functional recovery from ischemia in vitro and protects against myocardial infarction in vivo. J Biol Chem. 280:669–676. 2005. View Article : Google Scholar
23	Karwatowski SP, Mohiaddin RH, Yang GZ, Firmin DN, St John Sutton M and Underwood SR: Regional myocardial velocity imaged by magnetic resonance in patients with ischaemic heart disease. Br Heart J. 72:332–338. 1994. View Article : Google Scholar : PubMed/NCBI
24	Schröder M and Kaufman RJ: The mammalian unfolded protein response. Annu Rev Biochem. 74:739–789. 2005. View Article : Google Scholar : PubMed/NCBI
25	Thuerauf DJ, Marcinko M, Gude N, Rubio M, Sussman MA and Glembotski CC: Activation of the unfolded protein response in infarcted mouse heart and hypoxic cultured cardiac myocytes. Circ Res. 99:275–282. 2006. View Article : Google Scholar : PubMed/NCBI
26	Ron D and Walter P: Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 8:519–529. 2007. View Article : Google Scholar : PubMed/NCBI
27	Walter P and Ron D: The unfolded protein response: from stress pathway to homeostatic regulation. Science. 334:1081–1086. 2011. View Article : Google Scholar : PubMed/NCBI
28	Nakagawa T, Zhu H, Morishima N, et al: Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature. 403:98–103. 2000. View Article : Google Scholar : PubMed/NCBI
29	Oyadomari S and Mori M: Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 11:381–389. 2004. View Article : Google Scholar
30	Benavides A, Pastor D, Santos P, Tranque P and Calvo S: CHOP plays a pivotal role in the astrocyte death induced by oxygen and glucose deprivation. Glia. 52:261–275. 2005. View Article : Google Scholar : PubMed/NCBI
31	Prabhu S, Jainu M, Sabitha KE and Devi CS: Role of mangiferin on biochemical alterations and antioxidant status in isoproterenol-induced myocardial infarction in rats. J Ethnopharmacol. 107:126–133. 2006. View Article : Google Scholar : PubMed/NCBI
32	Boyce M, Bryant KF, Jousse C, et al: A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science. 307:935–939. 2005. View Article : Google Scholar : PubMed/NCBI
33	Komoike Y, Inamura H and Matsuoka M: Effects of salubrinal on cadmium-induced apoptosis in HK-2 human renal proximal tubular cells. Arch Toxicol. 86:37–44. 2012. View Article : Google Scholar
34	George I, Sabbah HN, Xu K, Wang N and Wang J: β-Adrenergic receptor blockade reduces endoplasmic reticulum stress and normalizes calcium handling in a coronary embolization model of heart failure in canines. Cardiovasc Res. 91:447–455. 2011. View Article : Google Scholar : PubMed/NCBI