Activation of protein kinase C‑α/heme oxygenase‑1 signaling pathway improves mitochondrial dynamics in lipopolysaccharide‑activated NR8383 cells

Li,Xiangyun; Zhang,Yuan; Yu,Jianbo; Mu,Rui; Wu,Lili; Shi,Jia; Gong,Lirong; Liu,Daquan

doi:10.3892/etm.2018.6290

Activation of protein kinase C‑α/heme oxygenase‑1 signaling pathway improves mitochondrial dynamics in lipopolysaccharide‑activated NR8383 cells

Authors:
- Xiangyun Li
- Yuan Zhang
- Jianbo Yu
- Rui Mu
- Lili Wu
- Jia Shi
- Lirong Gong
- Daquan Liu
View Affiliations

Affiliations: Department of Anesthesiology, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, P.R. China, Department of Pharmacology, Institute of Integrated Traditional Chinese and Western Medicine for Acute Abdominal Diseases, Tianjin 300100, P.R. China
Published online on: June 12, 2018 https://doi.org/10.3892/etm.2018.6290
Pages: 1529-1537

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

Mitochondrial function and morphology are dynamically regulated by fusion and fission. Heme oxygenase‑1 (HO‑1), which may be upregulated by protein kinase C‑α (PKC‑α), improves mitochondrial dynamics by controlling the balance between fusion and fission in vivo and in vitro. However, whether the PKC‑α/HO‑1 signaling pathway is one of the underlying mechanisms in adjusting mitochondrial dynamics in lipopolysaccharide (LPS)‑activated macrophages has remained elusive. To explore this, NR8383 cells were pre‑treated with PKC‑α inhibitor Go6976 or PKC‑α activator phorbol‑12‑myristate‑13‑acetate for 30 min and then stimulated with LPS for 24 h. Next, the expression of PKC‑α, HO‑1, mitofusin 1 (Mfn1) and mitofusin 2 (Mfn2), optic atrophy 1 (OPA1), dynamin‑related protein 1 (Drp1) and fission 1 (Fis1) was detected to evaluate the possible implication of the PKC‑α/HO‑1 signaling pathway in the LPS‑induced NR8383 cells. The results indicated that activation of the PKC‑α/HO‑1 signaling pathway increased superoxide dismutase activities and the respiratory control ratio (RCR), decreased the levels of malondialdehyde, reactive oxygen species (ROS), Drp1 and Fis1, and simultaneously enhanced the levels of Mfn1, Mfn2 and OPA1. In contrast, the PKC‑α inhibitor decreased the expression of RCR, Mfn1, Mfn2 and OPA1, and increased the expression of MDA and ROS in NR8383 cells. The results suggest that activation of the PKC‑α/HO‑1 signaling pathway is necessary for the balance of mitochondrial dynamics and oxidative stress in macrophages, which provides clues for probing novel strategies against the detrimental effects of sepsis and other disease states.

View Figures

View References

1	DeBalsi KL, Hoff KE and Copeland WC: Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases. Ageing Res Rev. 33:89–104. 2017. View Article : Google Scholar : PubMed/NCBI
2	Sheridan C and Martin SJ: Mitochondrial fission/fusion dynamics and apoptosis. Mitochondrion. 10:640–648. 2010. View Article : Google Scholar : PubMed/NCBI
3	Kieper N, Holmström KM, Ciceri D, Fiesel FC, Wolburg H, Ziviani E, Whitworth AJ, Martins LM, Kahle PJ and Krüger R: Modulation of mitochondrial function and morphology by interaction of Omi/HtrA2 with the mitochondrial fusion factor OPA1. Exp Cell Res. 316:1213–1224. 2010. View Article : Google Scholar : PubMed/NCBI
4	Yu J, Wu J, Xie P, Maimaitili Y, Wang J, Xia Z, Gao F, Zhang X and Zheng H: Sevoflurane postconditioning attenuates cardiomyocyte hypoxia/reoxygenation injury via restoring mitochondrial morphology. PeerJ. 4:e26592016. View Article : Google Scholar : PubMed/NCBI
5	Zhuang X, Maimaitijiang A, Li Y, Shi H and Jiang X: Salidroside inhibits high-glucose induced proliferation of vascular smooth muscle cells via inhibiting mitochondrial fission and oxidative stress. Exp Ther Med. 14:515–524. 2017. View Article : Google Scholar : PubMed/NCBI
6	Zhang Q, Tamura Y, Roy M, Adachi Y, Iijima M and Sesaki H: Biosynthesis and roles of phospholipids in mitochondrial fusion, division and mitophagy. Cell Mol Life Sci. 71:3767–3778. 2014. View Article : Google Scholar : PubMed/NCBI
7	Lin L, Zhang M, Yan R, Shan H, Diao J and Wei J: Inhibition of Drp1 attenuates mitochondrial damage and myocardial injury in Coxsackievirus B3 induced myocarditis. Biochem Biophys Res Commun. 484:550–556. 2017. View Article : Google Scholar : PubMed/NCBI
8	Han XJ, Tomizawa K, Fujimura A, Ohmori I, Nishiki T, Matsushita M and Matsui H: Regulation of mitochondrial dynamics and neurodegenerative diseases. Acta medica Okayama. 65:1–10. 2011.PubMed/NCBI
9	Hu C, Huang Y and Li L: Drp1-dependent mitochondrial fission plays critical roles in physiological and pathological progresses in mammals. Int J Mol Sci. 18:pii: E144. 2017. View Article : Google Scholar
10	Rayamajhi N, Kim SK, Go H, Joe Y, Callaway Z, Kang JG, Ryter SW and Chung HT: Quercetin induces mitochondrial biogenesis through activation of HO-1 in HepG2 cells. Oxid Med Cell Longev. 2013:1542792013. View Article : Google Scholar : PubMed/NCBI
11	Yu JB, Zhou F, Yao SL, Tang ZH, Wang M and Chen HR: Effect of heme oxygenase-1 on the kidney during septic shock in rats. Transl Res. 153:283–287. 2009. View Article : Google Scholar : PubMed/NCBI
12	Constantin M, Choi AJ, Cloonan SM and Ryter SW: Therapeutic potential of heme oxygenase-1/carbon monoxide in lung disease. Int J Hypertens. 2012:8592352012. View Article : Google Scholar : PubMed/NCBI
13	Loboda A, Damulewicz M, Pyza E, Jozkowicz A and Dulak J: Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci. 73:3221–3247. 2016. View Article : Google Scholar : PubMed/NCBI
14	Lee SE, Yang H, Son GW, Park HR, Park CS, Jin YH and Park YS: Eriodictyol protects endothelial cells against oxidative stress-induced cell death through modulating ERK/Nrf2/ARE-Dependent heme oxygenase-1 expression. Int J Mol Sci. 16:14526–14539. 2015. View Article : Google Scholar : PubMed/NCBI
15	Lin YT, Chen YH, Yang YH, Jao HC, Abiko Y, Yokoyama K and Hsu C: Heme oxygenase-1 suppresses the infiltration of neutrophils in rat liver during sepsis through inactivation of p38 MAPK. Shock. 34:615–621. 2010. View Article : Google Scholar : PubMed/NCBI
16	Fredenburgh LE, Perrella MA and Mitsialis SA: The role of heme oxygenase-1 in pulmonary disease. The role of heme oxygenase-1 in pulmonary disease. 36:158–165. 2007.
17	Liu XM, Peyton KJ and Durante W: Ammonia promotes endothelial cell survival via the heme oxygenase-1-mediated release of carbon monoxide. Free Radic Biol Med. 102:37–46. 2017. View Article : Google Scholar : PubMed/NCBI
18	MacGarvey NC, Suliman HB, Bartz RR, Fu P, Withers CM, Welty-Wolf KE and Piantadosi CA: Activation of mitochondrial biogenesis by heme oxygenase-1-mediated NF-E2-related factor-2 induction rescues mice from lethal Staphylococcus aureus sepsis. Am J Respir Crit Care Med. 185:851–861. 2012. View Article : Google Scholar : PubMed/NCBI
19	Yu JB and Yao SL: Effect of heme oxygenase-endogenous carbon monoxide on mortality during septic shock in rats. Ir J Med Sci. 178:491–496. 2009. View Article : Google Scholar : PubMed/NCBI
20	Yu J, Wang Y, Li Z, Dong S, Wang D, Gong L, Shi J, Zhang Y, Liu D and Mu R: Effect of heme oxygenase-1 on mitofusin-1 protein in LPS-induced ALI/ARDS in rats. Sci Rep. 6:365302016. View Article : Google Scholar : PubMed/NCBI
21	Yu J, Shi J, Wang D, Dong S, Zhang Y, Wang M, Gong L, Fu Q and Liu D: Heme oxygenase-1/carbon monoxide-regulated mitochondrial dynamic equilibrium contributes to the attenuation of endotoxin-induced acute lung injury in rats and in lipopolysaccharide-activated macrophages. Anesthesiology. 125:1190–1201. 2016. View Article : Google Scholar : PubMed/NCBI
22	Wang G, Chen Z, Zhang F, Jing H, Xu W, Ning S, Li Z, Liu K, Yao J and Tian X: Blockade of PKCβ protects against remote organ injury induced by intestinal ischemia and reperfusion via a p66shc-mediated mitochondrial apoptotic pathway. Apoptosis. 19:1342–1353. 2014. View Article : Google Scholar : PubMed/NCBI
23	Hug H and Sarre TF: Protein kinase C isoenzymes: Divergence in signal transduction? Biochem J. 291:329–343. 1993. View Article : Google Scholar : PubMed/NCBI
24	Zhou H, Wang Y, Zhou Q, Wu B, Wang A, Jiang W and Wang L: Down-regulation of protein kinase C-ε by prolonged incubation with PMA inhibits the proliferation of vascular smooth muscle cells. Cell Physiol Biochem. 40:379–390. 2016. View Article : Google Scholar : PubMed/NCBI
25	Rushworth SA, Chen XL, Mackman N, Ogborne RM and O'Connell MA: Lipopolysaccharide-induced heme oxygenase-1 expression in human monocytic cells is mediated via Nrf2 and protein kinase C. J Immunol. 175:4408–4415. 2005. View Article : Google Scholar : PubMed/NCBI
26	Yuan ZH, Liang ZE, Wu J, Yi JE, Chen XJ and Sun ZL: A potential mechanism for the anti-apoptotic property of koumine involving mitochondrial pathway in LPS-mediated RAW 264.7 macrophages. Molecules. 21:pii: E1317. 2016. View Article : Google Scholar
27	Carlson DE, Pumplin DW, Ghavam S, Fiedler SM, Chiu WC and Scalea TM: ATP accelerates respiration of mitochondria from rat lung and suppresses their release of hydrogen peroxide. J Bioenerg Biomembr. 37:327–338. 2005. View Article : Google Scholar : PubMed/NCBI
28	Labieniec-Watala M, Siewiera K and Jozwiak Z: Resorcylidene aminoguanidine (RAG) improves cardiac mitochondrial bioenergetics impaired by hyperglycaemia in a model of experimental diabetes. Int J Mol Sci. 12:8013–8026. 2011. View Article : Google Scholar : PubMed/NCBI
29	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
30	Balogun E, Hoque M, Gong P, Killeen E, Green CJ, Foresti R, Alam J and Motterlini R: Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. Biochem J. 371:887–895. 2003. View Article : Google Scholar : PubMed/NCBI
31	Jacoby RP, Millar AH and Taylor NL: Assessment of respiration in isolated plant mitochondria using Clark-type electrodes. Methods Mol Biol. 1305:165–185. 2015. View Article : Google Scholar : PubMed/NCBI
32	Chi X, Guo N, Yao W, Jin Y, Gao W, Cai J and Hei Z: Induction of heme oxygenase-1 by hemin protects lung against orthotopic autologous liver transplantation-induced acute lung injury in rats. J Transl Med. 14:352016. View Article : Google Scholar : PubMed/NCBI
33	Hull TD, Boddu R, Guo L, Tisher CC, Traylor AM, Patel B, Joseph R, Prabhu SD, Suliman HB, Piantadosi CA, et al: Heme oxygenase-1 regulates mitochondrial quality control in the heart. JCI insight. 1:e858172016. View Article : Google Scholar : PubMed/NCBI
34	Zhong ZY and Tang Y: Upregulation of periostin prevents high glucose-induced mitochondrial apoptosis in human umbilical vein endothelial cells via activation of Nrf2/HO-1 signaling. Cell Physiol Biochem. 39:71–80. 2016. View Article : Google Scholar : PubMed/NCBI
35	Ding X, Jin S, Tong Y, Jiang X, Chen Z, Mei S, Zhang L, Billiar TR and Li Q: TLR4 signaling induces TLR3 up-regulation in alveolar macrophages during acute lung injury. Sci Rep. 7:342782017. View Article : Google Scholar : PubMed/NCBI
36	Guha M and Mackman N: LPS induction of gene expression in human monocytes. Cell Signal. 13:85–94. 2001. View Article : Google Scholar : PubMed/NCBI
37	Lee TY, Lee KC, Chen SY and Chang HH: 6-Gingerol inhibits ROS and iNOS through the suppression of PKC-alpha and NF-kappaB pathways in lipopolysaccharide-stimulated mouse macrophages. Biochem Biophys Res Commun. 382:134–139. 2009. View Article : Google Scholar : PubMed/NCBI
38	Zhang Z, Cui W, Li G, Yuan S, Xu D, Hoi MP, Lin Z, Dou J, Han Y and Lee SM: Baicalein protects against 6-OHDA-induced neurotoxicity through activation of Keap1/Nrf2/HO-1 and involving PKCα and PI3K/AKT signaling pathways. J Agric Food Chem. 60:8171–8182. 2012. View Article : Google Scholar : PubMed/NCBI
39	Lin M, Zhai X, Wang G, Tian X, Gao D, Shi L, Wu H, Fan Q, Peng J4, Liu K and Yao J: Salvianolic acid B protects against acetaminophen hepatotoxicity by inducing Nrf2 and phase II detoxification gene expression via activation of the PI3K and PKC signaling pathways. J Pharmacol Sci. 127:203–210. 2015. View Article : Google Scholar : PubMed/NCBI
40	Lee H, Park YH, Jeon YT, Hwang JW, Lim YJ, Kim E, Park SY and Park HP: Sevoflurane post-conditioning increases nuclear factor erythroid 2-related factor and haemoxygenase-1 expression via protein kinase C pathway in a rat model of transient global cerebral ischaemia. Br J Anaesth. 114:307–318. 2015. View Article : Google Scholar : PubMed/NCBI