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Apelin‑13 Attenuates ER Stress‑Associated Apoptosis Induced by MPP+ in SH‑SY5Y Cells

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Apelin‑13 Attenuates ER Stress‑Associated Apoptosis Induced by MPP+ in SH‑SY5Y Cells 1732 INTERNATIONAL JOURNAL OF MOleCular meDICine 42: 1732-1740, 2018 Apelin‑13 attenuates ER stress‑associated apoptosis induced by MPP+ in SH‑SY5Y cells YUNLU JIANG1, HAIQING LIU2, BINGYUAN JI1, ZHENGWEN WANG1, CHUNMEI WANG1, CHUNQING YANG1, YANYOU PAN1, JING CHEN3, BAOHUA CHENG1 and BO BAI1 1Neurobiology Institute, Jining Medical University, Jining, Shandong 272067; 2Department of Physiology, Taishan Medical College, Taian, Shandong 271000, P.R. China; 3Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK Received October 12, 2017; Accepted May 31, 2018 DOI: 10.3892/ijmm.2018.3719 Abstract. Apelin-13, a neuropeptide that acts as a ligand for GRP78, CHOP and cleaved caspase-12 in MPP+-treated a putative receptor related to the angiotensin II type receptor, SH‑SY5Y cells, and significantly enhanced the expression elicits neuroprotective effects in numerous neurological condi- levels of phospho-ERK1/2. Taken together, the present results tions, such as Huntington's disease and cerebral ischemia. support a model in which apelin-13 inhibits MPP+-induced Parkinson's disease (PD), one of the most prevalent neuro- apoptosis of SH-SY5Y cells by decreasing the expression of degenerative diseases, is caused by damage to neurons in the GRP78, CHOP, and cleaved caspase-12, and by increasing the brain; however, the underlying mechanism remains unclear. expression of phospho-ERK1/2. The present findings suggest The present study explored the effects of apelin-13 on SH-SY5Y that apelin-13 may be useful for the treatment of PD. human neuroblastoma cells treated with 1-methyl-4-phenyl- pyridine (MPP+). Cell growth, cell viability, and apoptosis Introduction were measured by real-time cell analysis, the Cell Counting Kit-8 assay, and flow cytometry, respectively. In addition, Parkinson's disease (PD) is the second most prevalent neuro- the expression levels of extracellular signal-regulated kinase degenerative disease worldwide and is characterized by (ERK) 1/2, p38 mitogen-activated protein kinase (MAPK), bradykinesia, muscle rigidity, and reduced independence (1-3). glucose-regulated protein 78 (GRP78), C/EBP homologous Oxidative stress, aging, infection, genetic and environmental protein (CHOP), and cleaved caspase-12 were assessed by factors are considered major causes of PD (4-7). However, the western blotting. MPP+ treatment decreased the viability of pathogenesis of the disease is not fully understood. SH-SY5Y cells and increased their apoptosis; however, these The endoplasmic reticulum (ER) is a major subcellular changes were attenuated by pretreatment with apelin-13. organelle and serves an important role in various cellular func- Treatment with MPP+ for 24 h significantly increased the tions, including protein folding, protein trafficking and steroid expression levels of phospho-ERK1/2, phospho-p38, GRP78, and lipid metabolism (8-10). Multiple factors, such as oxidative CHOP, and cleaved caspase-12 in SH-SY5Y cells. Pretreatment stress and ischemia-reperfusion (I/R) injury, can induce the with apelin-13 significantly attenuated the upregulation of release of inflammatory cytokines and lead to ER stress (11). ER stress is a widely used marker of PD and is also closely related to other neurological disorders, such as Huntington's disease and Alzheimer's disease (AD) (10). Investigation of Correspondence to: Professor Bo Bai or Professor Baohua Cheng, the mechanism underlying ER stress in PD may lead to the Neurobiology Institute, Jining Medical University, 133 Hehua Road, development of new therapeutic strategies. Jining, Shandong 272067, P.R. China Apelin, a neuropeptide that acts as a ligand for the orphan E-mail: [email protected] G protein-coupled apelin receptor (APJ), has been extracted E-mail: [email protected] from bovine stomach tissue and undergoes cleavage to generate apelin-13, -17 and -36 (12-14). Apelin peptides are Abbreviations: AD, Alzheimer's disease; CCK-8, Cell Counting associated with neuroprotection and cytoprotection. Apelin-13 Kit-8; ER, endoplasmic reticulum; ERK1/2, extracellular reduces the cerebral infarct volume in a middle cerebral artery signal-regulated kinase 1/2; GRP78, glucose-regulated protein 78; occlusion rat model by downregulating expression of inflam- I/R, ischemia-reperfusion; MAPK, mitogen-activated protein kinase; MPP+, 1-methyl-4-phenylpyridine; NMDA, N-methyl‑D‑aspartic acid; matory factors (15). In addition, the activity of apelin-13 is PI3K, phosphoinositide 3-kinase; Akt, AKT serine/threonine kinase 1; higher compared with apelin-17 and -36 (14-16). Apelin-36, PD, Parkinson's disease; RTCA, real-time cell analysis a long apelin peptide, protects against ischemic brain injury by decreasing the levels of caspase-3 and BCL2 associated X Key words: apelin-13, Parkinson's disease, glucose-regulated protein 78, (Bax), which are well-established apoptotic markers, thereby neuroprotection reducing neurological deficits (17). Furthermore, treatment with apelin-13 markedly decreases brain edema and the JIANG et al: APELIN-13 PROTECTS AGAINST MPP+ INDUCED NEUROTOXICITY 1733 total infarct volume and suppresses apoptosis by reducing a microplate reader. Cell viability was calculated using the caspase-3 activation (18). Our previous study has demonstrated following formula: Cell viability (%)=(A-B)/(A'-B) x100, where that apelin-13 protects against cerebral I/R injury (15), consis- A is the average absorbance of wells containing the indicated tent with other literature. However, the mechanism by which drugs, SH-SY5Y cells, and CCK-8 solution; A' is the average apelin protects neurons against 1-methyl-4-phenylpyridine absorbance of wells containing SH-SY5Y cells and CCK-8 (MPP+)-induced apoptosis in a cellular model of PD remain solution; and B is the average absorbance of wells containing unclear. The present study investigated the effects of apelin-13 medium and CCK-8 solution. on MPP+-treated SH-SY5Y cells, a cellular model of PD, and the underlying molecular mechanism. Flow cytometry. SH-SY5Y cells (5x105 cells/well) were collected by centrifugation (800 x g for 5 min at room temper- Materials and methods ature), treated with MPP+ for 24 h, and washed with PBS. Thereafter, 500 µl of Annexin V binding buffer (Biouniquer Reagents and cell culture. Human apelin-13 [half maximal Technology, Beijing, China) was added to each cell suspen- effective concentration (EC50)=0.37 nM (19)] was obtained sion followed by 5 µl of Annexin V‑fluorescein isothiocyanate from Phoenix Pharmaceuticals (St. Joseph, MO, USA). Its (FITC) and 5 µl of propidium iodide for 5 min. A total of amino acid sequence is Gln-Arg-Pro-Arg-Leu-Ser-His-L 10,000 cells were analyzed per sample by flow cytometry, ys-Gly-Pro -Met-Pro-Phe (20). MPP+ iodide and the Cell which was performed using a BD FACSCalibur flow cytometer Counting Kit-8 (CCK-8) were obtained from Sigma-Aldrich; (BD Biosciences, Franklin Lakes, NJ, USA), using an excitation Merck KGaA (Darmstadt, Germany). Antibodies against p38 wavelength of 488 nm and an emission wavelength of 530 nm. mitogen-activated protein kinase (MAPK; cat. no. 8690), Data are representative of at least three independent experi- phosphorylated (phospho)-p38 MAPK (cat. no. 4511), extra- ments. The results were analyzed using BD CellQuest Pro cellular signal-regulated kinase (ERK) 1/2 (cat. no. 4696), software (version 5.1; BD Biosciences). phospho-ERK1/2 (cat. no. 9101), glucose-regulated protein 78 (GRP78, also known as BiP; cat. no. 3183), C/EBP homologous Western blotting. SH-SY5Y cells were transferred to 6-well protein (CHOP; cat. no. 2895), and caspase-12 (cat. no. 2202) plates and incubated overnight in the presence of 5% CO2 at were obtained from Cell Signaling Technology, Inc. (Danvers, 37˚C. Thereafter, cells were treated with 0, 100, 250, 500, 750 MA, USA). Anti-β-actin primary antibody (cat. no. TA-09), or 1,000 µM MPP+ for 24 h with or without 100 nM apelin-13, polyclonal goat anti-mouse (cat. no. ZB-2305) and anti-rabbit washed with ice-cold PBS, and lysed in RIPA buffer. Cells secondary antibodies (cat. no. ZB-2301) were obtained were collected in clean 1.5 ml centrifuge tubes and cleared from OriGene Technologies, Inc. (Beijing, China) (21). The by centrifugation at 1,200 x g for 35 min at 4˚C. The protein SH-SY5Y cell line was obtained from the American Type concentration was determined by the bicinchoninic acid assay, Culture Collection (Manassas, VA, USA) (22-24) and routinely using bovine serum albumin as a standard. Equal amounts cultured in DMEM supplemented with 10% fetal bovine serum (35 µg) of cell extracts were analyzed by 10% SDS-PAGE. (FBS; Gibco; Thermo Fisher Scientific, Inc., Waltham, MA, Separated proteins were transferred to polyvinylidene USA) and 100 U/ml penicillin/streptomycin in the presence of fluoride membranes at 300 mA for 40‑80 min. Membranes 5% CO2 at 37˚C. were blocked with TBS/0.1% Tween-20 (TBST) containing 5% milk at room temperature for 1 h, rinsed thrice with Real‑time cell analysis (RTCA). Real-time cell analysis TBST for 10 min, and incubated overnight at 4˚C with rabbit (RTCA) (25) was performed to study the effects of MPP+ on anti-phospho-p38 (1:1,000), rabbit anti-phospho-ERK1/2 SH-SY5Y cells. Each well of an E-Plate 16 was incubated with (1:2,000), rabbit anti-GRP78 (1:1,000), mouse anti‑CHOP 100 µl of culture media for 30 min at 37˚C to ensure substrate (1:1,000), and rabbit anti-caspase-12 (1:1,000) antibodies. equilibrium; this background step was crucial. Next, SH-SY5Y Thereafter, membranes were washed with TBST and incubated cells were digested with 0.25% trypsin/0.02% EDTA solu- with appropriate secondary antibodies [goat anti-rabbit-IgG tion, and 100 µl of culture media containing 5x104 cells was (1:5,000) for phospho-ERK1/2, phospho-p38, GRP78, and added to each well of the E-Plate 16 and incubated overnight caspase-12, and goat anti-mouse-IgG (1:5,000) for CHOP] at 37˚C.
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