Minocycline induces protective autophagy in vascular endothelial cells exposed to an in vitro model of ischemia/reperfusion‑induced injury

Dong,Wenbin; Xiao,Shigeng; Cheng,Min; Ye,Xiaodi; Zheng,Gaoli

doi:10.3892/br.2015.554

Minocycline induces protective autophagy in vascular endothelial cells exposed to an in vitro model of ischemia/reperfusion‑induced injury

Authors:
- Wenbin Dong
- Shigeng Xiao
- Min Cheng
- Xiaodi Ye
- Gaoli Zheng
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Affiliations: Institute of Materia Medica, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang 310013, P.R. China
Published online on: December 10, 2015 https://doi.org/10.3892/br.2015.554
Pages: 173-177
Copyright: © Dong et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Minocycline has been reported to exhibit advantageous effects on ischemic stroke; however, the precise mechanism of minocycline remains to be established. In the present study, human umbilical vein endothelial cells (HUVECs) were subjected to in vitro simulated ischemia/reperfusion conditions to determine the potential effect of minocycline‑induced autophagy on HUVEC damage under oxygen‑glucose deprivation/reperfusion (OGD/R). The study demonstrated that minocycline enhanced autophagy in a dose‑dependent manner in HUVECs exposed to OGD/R, and only low‑dose minocycline protected HUVECs from OGD/R‑induced damage. Subsequently, 3‑methyladenine (3‑MA) was added into the culture media and the protective effect of minocycline was abolished. At the same time, it has been observed that simultaneous treatment with 3‑MA also inhibited the autophagy activity induced by minocycline. This finding could suggest that autophagy induced by minocycline serves as one of the potential protective mechanism underlying the beneficial effects of minocycline on ischemic injury.

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1	Lo EH: A new penumbra: T ransitioning from injury into repair after stroke. Nat Med. 14:497–500. 2008. View Article : Google Scholar : PubMed/NCBI
2	Lee SR, Wang X, Tsuji K and Lo EH: Extracellular proteolytic pathophysiology in the neurovascular unit after stroke. Neurol Res. 26:854–861. 2004. View Article : Google Scholar : PubMed/NCBI
3	Moroni F and Chiarugi A: Post-ischemic brain damage: Targeting PARP-1 within the ischemic neurovascular units as a realistic avenue to stroke treatment. FEBS J. 276:36–45. 2009. View Article : Google Scholar : PubMed/NCBI
4	Curin Y, Ritz MF and Andriantsitohaina R: Cellular mechanisms of the protective effect of polyphenols on the neurovascular unit in strokes. Cardiovasc Hematol Agents Med Chem. 4:277–288. 2006. View Article : Google Scholar : PubMed/NCBI
5	Xie R, Li X, Ling Y, Shen C, Wu X, Xu W and Gao X: Alpha-lipoic acid pre- and post-treatments provide protection against in vitro ischemia-reperfusion injury in cerebral endothelial cells via Akt/mTOR signaling. Brain Res. 1482:81–90. 2012. View Article : Google Scholar : PubMed/NCBI
6	Olmez I and Ozyurt H: Reactive oxygen species and ischemic cerebrovascular disease. Neurochem Int. 60:208–212. 2012. View Article : Google Scholar : PubMed/NCBI
7	Sandoval KE and Witt KA: Blood-brain barrier tight junction permeability and ischemic stroke. Neurobiol Dis. 32:200–219. 2008. View Article : Google Scholar : PubMed/NCBI
8	Buller KM, Carty ML, Reinebrant HE and Wixey JA: Minocycline: A neuroprotective agent for hypoxic-ischemic brain injury in the neonate. J Neurosci Res. 87:599–608. 2009. View Article : Google Scholar : PubMed/NCBI
9	Stirling DP, Koochesfahani KM, Steeves JD and Tetzlaff W: Minocycline as a neuroprotective agent. Neuroscientist. 11:308–322. 2005. View Article : Google Scholar : PubMed/NCBI
10	Switzer JA, Hess DC, Ergul A, Waller JL, Machado LS, Portik-Dobos V, Pettigrew LC, Clark WM and Fagan SC: Matrix metalloproteinase-9 in an exploratory trial of intravenous minocycline for acute ischemic stroke. Stroke. 42:2633–2635. 2011. View Article : Google Scholar : PubMed/NCBI
11	Mizushima N, Levine B, Cuervo AM and Klionsky DJ: Autophagy fights disease through cellular self-digestion. Nature. 451:1069–1075. 2008. View Article : Google Scholar : PubMed/NCBI
12	Gabryel B, Kost A and Kasprowska D: Neuronal autophagy in cerebral ischemia-a potential target for neuroprotective strategies. Pharmacol Rep. 64:1–15. 2012. View Article : Google Scholar : PubMed/NCBI
13	Rami A, Langhagen A and Steiger S: Focal cerebral ischemia induces upregulation of Beclin 1 and autophagy-like cell death. Neurobiol Dis. 29:132–141. 2008. View Article : Google Scholar : PubMed/NCBI
14	Urbanek T, Kuczmik W, Basta-Kaim A and Gabryel B: Rapamycin induces of protective autophagy in vascular endothelial cells exposed to oxygen-glucose deprivation. Brain Res. 1553:1–11. 2014. View Article : Google Scholar : PubMed/NCBI
15	Han J, Pan XY, Xu Y, Xiao Y, An Y, Tie L, Pan Y and Li XJ: Curcumin induces autophagy to protect vascular endothelial cell survival from oxidative stress damage. Autophagy. 8:812–825. 2012. View Article : Google Scholar : PubMed/NCBI
16	Liu WT, Lin CH, Hsiao M and Gean PW: Minocycline inhibits the growth of glioma by inducing autophagy. Autophagy. 7:166–175. 2011. View Article : Google Scholar : PubMed/NCBI
17	Ma X, Zhang H, Pan Q, Zhao Y, Chen J, Zhao B and Chen Y: Hypoxia/Aglycemia-induced endothelial barrier dysfunction and tight junction protein downregulation can be ameliorated by citicoline. PLoS One. 8:e826042013. View Article : Google Scholar : PubMed/NCBI
18	Liberio MS, Sadowski MC, Nelson CC and Davis RA: Identification of eusynstyelamide B as a potent cell cycle inhibitor following the generation and screening of an ascidian-derived extract library using a real time cell analyzer. Mar Drugs. 12:5222–5239. 2014. View Article : Google Scholar : PubMed/NCBI
19	Klionsky DJ, Abdalla FC, Abeliovich H, Abraham RT, Acevedo-Arozena A, Adeli K, Agholme L, Agnello M, Agostinis P, Aguirre-Ghiso JA, et al: Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 8:445–544. 2012. View Article : Google Scholar : PubMed/NCBI
20	Carloni S, Buonocore G and Balduini W: Protective role of autophagy in neonatal hypoxia-ischemia induced brain injury. Neurobiol Dis. 32:329–339. 2008. View Article : Google Scholar : PubMed/NCBI
21	Alirezaei M, Kemball CC and Whitton JL: Autophagy, inflammation and neurodegenerative disease. Eur J Neurosci. 33:197–204. 2011. View Article : Google Scholar : PubMed/NCBI
22	Ferguson CJ, Lenk GM and Meisler MH: Defective autophagy in neurons and astrocytes from mice deficient in PI(3,5)P2. Hum Mol Genet. 18:4868–4878. 2009. View Article : Google Scholar : PubMed/NCBI
23	Adhami F, Schloemer A and Kuan CY: The roles of autophagy in cerebral ischemia. Autophagy. 3:42–44. 2007. View Article : Google Scholar : PubMed/NCBI
24	Zhang X, Yan H, Yuan Y, Gao J, Shen Z, Cheng Y, Shen Y, Wang RR, Wang X, Hu WW, et al: Cerebral ischemia-reperfusion-induced autophagy protects against neuronal injury by mitochondrial clearance. Autophagy. 9:1321–1333. 2013. View Article : Google Scholar : PubMed/NCBI
25	Wei K, Wang P and Miao CY: A double-edged sword with therapeutic potential, An updated role of autophagy in ischemic cerebral injury. CNS Neurosci Ther. 18:879–886. 2012. View Article : Google Scholar : PubMed/NCBI