p38 MAPK‑MK2 pathway regulates the heat‑stress‑induced accumulation of reactive oxygen species that mediates apoptotic cell death in glial cells

Li,Hongbo; Liu,Yanan; Gu,Zhengtao; Li,Li; Liu,Yunsong; Wang,Lin; Su,Lei

doi:10.3892/ol.2017.7360

p38 MAPK‑MK2 pathway regulates the heat‑stress‑induced accumulation of reactive oxygen species that mediates apoptotic cell death in glial cells

Authors:
- Hongbo Li
- Yanan Liu
- Zhengtao Gu
- Li Li
- Yunsong Liu
- Lin Wang
- Lei Su
View Affiliations

Affiliations: Graduate School Department, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China, Department of Intensive Care Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China, Intensive Care Unit, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong 510630, P.R. China, Intensive Care Unit, General Hospital of Guangzhou Military Command, Key Laboratory of Tropical Zone Trauma Care and Tissue Repair of PLA, Guangzhou, Guangdong 510010, P.R. China, Emergency Department, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China
Published online on: November 8, 2017 https://doi.org/10.3892/ol.2017.7360
Pages: 775-782
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Previous studies have demonstratedf that heat stress can induce injury of the central nervous system and lead to neuronal cell apoptosis. However, the molecular mechanisms underlying these cellular changes remain unclear. In the present study, flow cytometry was used to investigate heat‑stress‑induced apoptosis, and caspase‑3 activation was also assessed in neurons. The role of reactive oxygen species (ROS) accumulation in the heat‑stress‑induced apoptosis of neurons was demonstrated using the antioxidant drug manganese (III) tetrakis (4‑benzoic acid)porphyrin. The present study presents evidence that heat stress induces mitogen‑activated protein kinase (MAPK) activation in rat malignant glioma F98 cells. Following the inhibition of different MAPKs with a range of specific inhibitors, SB203580 (an inhibitor of p38 MAPK), but not PD98059 (an inhibitor of extracellular signal‑regulated kinases) or SP600125 (an inhibitor of c‑Jun N‑terminal kinases), diminished the production of ROS and apoptosis, and prevented activation of the p38‑downstream kinase MAPK‑activated protein kinase 2 (MK2) in neurons. Inhibiting MK2 with dominant negative adenoviral constructs or a specific inhibitor significantly decreased normal and heat‑stress‑induced ROS accumulation and cell apoptosis, whereas inhibition of another kinase downstream of p38 MAPK, MAPK‑activated protein kinase 5, by transfection with another adenoviral construct did not exert the same effects. Taken together, these findings indicate that heat stress stimulation induces p38‑MK2 pathway activation, which exerts a pro‑apoptotic effect by regulating ROS accumulation in neurons.

View Figures

View References

1	Malamud N, Haymaker W and Custer RP: Heat stroke: A clinicoorgan pathological study of 125 fatal cases. Mil Surg. 99:394–449. 1946.
2	Hausfater P, Megarbane B, Dautheville S, Patzak A, Andronikof M, Santin A, André S, Korchia L, Terbaoui N, Kierzek G, et al: Prognostic factors in non-exertional heatstroke. Intensive Care Med. 36:272–280. 2010. View Article : Google Scholar : PubMed/NCBI
3	Dematte JE, O'Mara K, Buescher J, Whitney CG, Forsythe S, McNamee T, Adiga RB and Ndukwu IM: Near-fatal heat stroke during the 1995 heat wave in Chicago. Ann Intern Med. 129:173–181. 1998. View Article : Google Scholar : PubMed/NCBI
4	Mastrangelo G, Fedeli U, Visentin C, Milan G, Fadda E and Spolaore P: Pattern and determinants of hospitalization during heat waves: An ecologic study. BMC Public Health. 7:2002007. View Article : Google Scholar : PubMed/NCBI
5	Kovats RS and Kristie LE: Heatwaves and public health in Europe. Eur J Public Health. 16:592–599. 2006. View Article : Google Scholar : PubMed/NCBI
6	Edwards MJ, Walsh DA and Li Z: Hyperthermia, teratogenesis and the heat shock response in mammalian embryos in culture. Int J Dev Biol. 41:345–358. 1997.PubMed/NCBI
7	Yu J, Liu F, Yin P, Zhao H, Luan W, Hou X, Zhong Y, Jia D, Zan J, Ma W, et al: Involvement of oxidative stress and mitogen-activated protein kinase signaling pathways in heat stress-induced injury in the rat small intestine. Stress. 16:99–113. 2013. View Article : Google Scholar : PubMed/NCBI
8	Liu Y, Zhou G, Wang Z, Guo X, Xu Q, Huang Q and Su L: NF-κB signaling is essential for resistance to heat stress-induced early stage apoptosis in human umbilical vein endothelial cells. Sci Rep. 5:135472015. View Article : Google Scholar : PubMed/NCBI
9	Chang L and Karin M: Mammalian MAP kinase signalling cascades. Nature. 410:37–40. 2001. View Article : Google Scholar : PubMed/NCBI
10	Seger R and Krebs EG: The MAPK signaling cascade. FASEB J. 9:726–735. 1995.PubMed/NCBI
11	Roux PP and Blenis J: ERK and p38 MAPK-activated protein kinases: A family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev. 68:320–344. 2004. View Article : Google Scholar : PubMed/NCBI
12	Kim EK and Choi EJ: Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta. 1802:396–405. 2010. View Article : Google Scholar : PubMed/NCBI
13	Cargnello M and Roux PP: Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev. 75:50–83. 2011. View Article : Google Scholar : PubMed/NCBI
14	Gaestel M: MAPKAP kinases-MKs-two's company, three's a crowd. Nat Rev Mol Cell Biol. 7:120–30. 2006. View Article : Google Scholar : PubMed/NCBI
15	New L, Jiang Y, Zhao M, Liu K, Zhu W, Flood LJ, Kato Y, Parry GC and Han J: PRAK, a novel protein kinase regulated by the p38 MAP kinase. EMBO J. 17:3372–3384. 1998. View Article : Google Scholar : PubMed/NCBI
16	Liu R, Wu CX, Zhou D, Yang F, Tian S, Zhang L, Zhang TT and Du GH: Pinocembrin protects against β-amyloid-induced toxicity in neurons through inhibiting receptor for advanced glycation end products (RAGE)-independent signaling pathways and regulating mitochondrion-mediated apoptosis. BMC Med. 10:1052012. View Article : Google Scholar : PubMed/NCBI
17	Gu ZT, Wang H, Li L, Liu YS, Deng XB, Huo SF, Yuan FF, Liu ZF, Tong HS and Su L: Heat stress induces apoptosis through transcription-independent p53-mediated mitochondrial pathways in human umbilical vein endothelial cell. Sci Rep. 4:44692014. View Article : Google Scholar : PubMed/NCBI
18	Fiers W, Beyaert R, Declercq W and Vandenabeele P: More than one way to die: Apoptosis, necrosis and reactive oxygen damage. Oncogene. 18:7719–7730. 1999. View Article : Google Scholar : PubMed/NCBI
19	Sneed PK, Matsumato K, Stauffer PR, Fike JR, Smith V and Gutin PH: Interstitial microwave hyperthermia in a canine brain model. Int J Radiat Oncol Biol Phys. 12:1887–1897. 1986. View Article : Google Scholar : PubMed/NCBI
20	Wu W, Huan Q, Miao J, Xiao M, Liu H, Zhao K and Zhao M: MK2 plays an important role for the increased vascular permeability that follows thermal injury. Burns. 39:923–934. 2013. View Article : Google Scholar : PubMed/NCBI
21	Dorozynski A: Chirac announces investigation into heat wave's death toll. BMJ. 327:4652003. View Article : Google Scholar : PubMed/NCBI
22	Harris AB, Erickson L, Kendig JH, Mingrino S and Goldring S: Observations on selective brain heating in dogs. J Neurosurg. 19:514–521. 1962. View Article : Google Scholar : PubMed/NCBI
23	Burdon RH, Gill VM and Rice-Evans C: Oxidative stress and heat shock protein induction in human cells. Free Radic Res Commun. 3:129–139. 1987. View Article : Google Scholar : PubMed/NCBI
24	Skibba JL, Powers RH, Stadnicka A, Cullinane DW, Almagro UA and Kalbfleisch JH: Oxidative stress as a precursor to the irreversible hepatocellular injury caused by hyperthermia. Int J yperthermia. 7:749–761. 1991. View Article : Google Scholar
25	McAnulty SR, McAnulty L, Pascoe DD, Gropper SS, Keith RE, Morrow JD and Gladden LB: Hyperthermia increases exercise-induced oxidative stress. Int J Sports Med. 26:188–192. 2005. View Article : Google Scholar : PubMed/NCBI
26	Cuenda A and Rousseau S: p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta. 1773:1358–1375. 2007. View Article : Google Scholar : PubMed/NCBI
27	Cuadrado A and Nebreda AR: Mechanisms and functions of p38 MAPK signaling. Biochem J. 429:403–417. 2010. View Article : Google Scholar : PubMed/NCBI
28	Zhou J, Wan B, Liu XM, Li R, Wang Y and Yu L: MK5 is degraded in response to doxorubicin and negatively regulates doxorubicin-induced apoptosis in hepatocellular carcinoma cells. Biochem Biophys Res Commun. 427:581–586. 2012. View Article : Google Scholar : PubMed/NCBI