Non-coding RNAs: the extensive and interactive regulators of the blood-brain barrier permeability

Figures & data

Table 1. miRNAs as therapeutic targets of pharmacological agents for CNS injuries

CNS injuries	Cell/Animal species	miRNAs	Target mRNAs	References
Ischaemic stroke	Mice	miR-132	MMP-9	Zuo et al^[27].
	bEnd.3/Rats	miR-539	MMP-9	Fan et al^[28].
	Rats	miR-21	MAP2K3	Yao et al^[29].
	BMEC/Rats	miR-34a	Not investigated	Ren et al^[30].
	bEnd.3	miR-34a	Cytochrome c	Bukeirat et al^[31].
	Rats	miR-210	Occludin/β-catenin	Ma et al^[33].
	Human BMEC	miR-155	claudin-1	Philippides et al^[34].
	BMEC/Mice	miR-155	MFSD2A	Awad et al^[35].
	bEnd.3/ Mice	miR-182	mTOR/FOXO1	Zhang et al^[36].
	BMEC/Mice	miR-130a	HOXA5	Wang et al^[37].
	Rat BMEC	miR-150	Tie-2	Fang et al^[38].
	Mice	miR-15a	claudin-5	Ma et al^[39].
Haemorrhagic stroke	Rat BMEC/Rats	miR-126-3p	PIK3R2	Xi et al^[40].
	Rat BMEC/Rats	miR-27a-3p	AQP11	Xi et al^[41].
Traumatic brain injury	Mouse BMEC	miR-212/132	claudin-1/JAM3/TJP4	Burek et al^[42].
	Rat BMEC	miR-21	Angiopoietin-1/Tie-2	Ge et al^[43].
Multiple sclerosis	hCMEC/Mice	miR-155	annexin-2/claudin-1	Ramirez et al^[45].
	hCMEC	miR-125a-5p	VE-cadherin/ZO-1	Reijerkerk et al^[25].
Meningitis	Mouse BMEC	let-7/miR-98	CCL2/CCL5	Rom et al^[46].
	HUVEC/Monkeys	miR-1303	MMP-9	Song et al^[48].
	Human BMEC	miR-101	VE-cadherin	Mishra et al^[49].
	Mice	miR-155	Not investigated	Barker et al^[50].
Alzheimer′s Disease	hCMEC	miR-107	Endophilin-1	Liu et al^[51].
	hCMEC	miR-424-5p	Endophilin-1	Lin et al^[52].
	bEnd.3	miR-501-3p	ZO-1	Toyama et al^[53].
Diabetes	Mouse BMEC	let-7a	Not investigated	Song et al^[54].
	Rat BMEC	miR-200b	VEGFA	Yang et al^[55].
Hyperhomocysteinemia	bEnd.3/Mice	miR-29b	DNMT3B, MMP-9	Kalani et al^[56].
Methamphetamine	Human BMEC	miR-143	PUMA	Bai et al^[57].
Cancer	BMEC	miR-181 c	PDPK1	Tominaga et al^[58].

Figure 1. The structure of miRNAs, lncRNAs and circRNAs

Figure 2. A brief summary of miRNAs, lncRNAs and circRNAs as a factor controling BBB permeability

Table 2. Effects of lncRNAs and circRNAs on BBB dysfunction

CNS injuries	Cell/Animal species	lncRNAs/circRNAs	Molecular mechanisms	References
Alzheimer’s disease	hCMEC/pericytes co-culture	lnc00094	miR-224-5p (miR-497-5p)/Endophilin-1	Zhu et al^[78].
Ischaemic stroke	mouse BMEC	lncMALAT1	miR-145/VEGFA (ANGPT2)	Ren et al^[82].
	mouse BMEC and Mice	lncSNHG1	miR-18a (miR-199a)/HIF-1α/VEGF	Zhang et al^[83].
Haemorrhagic Stroke	Rat BMEC/Rats	lncSNHG3	TWEAK/Fn14/STAT3	Zhang et al^[80].
	BMEC/astrocytes co-culture and Mice	loc102640519	HOXC13	Wu et al^[85].
Glioma	hCMEC	piR-DQ590027	MIR17HG/miR-133 (miR-377)/FOXR2	Leng et al^[79].
	hCMEC/glioblastoma co-culture	lncMALAT1	miR-140/NFYA	Ma et al^[71].
	hCMEC/glioblastoma co-culture	lncNEAT1	miR-181d-5p/SOX5	Guo et al^[73].
	hCMEC/glioblastoma co-culture	lnc00174	miR-138-5p (miR-150-5p)/FOSL2	Guo et al^[74].
	hCMEC/glioblastoma co-culture	lncTUG1	miR-144/HSF2	Cai et al^[76].
	hCMEC/glioblastoma co-culture	circDENND4C	miR-577	Wu et al^[103].
Neuroinflammatory	Human BMEC and Mice	circHECW2	miR-30d/ATG5	Yang et al^[104].
Ischaemic stroke	bEnd.3 and Mice	circDLGAP4	miR-143/HECTD1	Bai et al^[105].
Bacterial meningitis	Human BMEC	circ2858	miR-93-5p/ VEGFA	Yang et al^[106].

Zuo X, Lu J, Manaenko A, et al. MicroRNA-132 attenuates cerebral injury by protecting blood-brain-barrier in MCAO mice. Exp Neurol. 2019;316:12–19.

 PubMed Web of Science ®Google Scholar

Fan F, Yang J, Xu Y, et al. MiR-539 targets MMP-9 to regulate the permeability of blood–brain barrier in ischemia/reperfusion injury of brain. Neurochem Res. 2018;43(12):2260–2267.

 PubMed Web of Science ®Google Scholar

Yao X, Wang Y, Zhang D. microRNA-21 Confers Neuroprotection against cerebral ischemia-reperfusion injury and alleviates blood-brain barrier disruption in rats via the MAPK signaling pathway. J Mol Neurosci. 2018;65(1):43–53.

 PubMed Web of Science ®Google Scholar

Ren X, Engler-Chiurazzi EB, Russell AE, et al. MiR-34a and stroke: assessment of non-modifiable biological risk factors in cerebral ischemia. Neurochem Int. 2019;127:73–79.

 PubMed Web of Science ®Google Scholar

Bukeirat M, Sarkar SN, Hu H, et al. MiR-34a regulates blood-brain barrier permeability and mitochondrial function by targeting cytochrome c. J Cereb Blood Flow Metab. 2016;36:387–392.

 PubMed Web of Science ®Google Scholar

Ma Q, Dasgupta C, Li Y, et al. MicroRNA-210 suppresses junction proteins and disrupts blood-brain barrier integrity in neonatal rat hypoxic-ischemic brain injury. Int J Mol Sci. 2017;18:1356.

 PubMed Web of Science ®Google Scholar

Pena-Philippides JC, Gardiner AS, Caballero-Garrido E, et al. Inhibition of microRNA-155 supports endothelial tight junction integrity following oxygen-glucose deprivation. J Am Heart Assoc. 2018;7:e009244.

 PubMed Web of Science ®Google Scholar

Awad H, Bratasz A, Nuovo G, et al. MiR-155 deletion reduces ischemia-induced paralysis in an aortic aneurysm repair mouse model: utility of immunohistochemistry and histopathology in understanding etiology of spinal cord paralysis. Ann Diagn Pathol. 2018;36:12–20.

 PubMed Web of Science ®Google Scholar

Zhang T, Tian C, Wu J, et al. MicroRNA-182 exacerbates blood-brain barrier (BBB) disruption by downregulating the mTOR/FOXO1 pathway in cerebral ischemia. FASEB J. 2020;34:13762–13775.

 PubMed Web of Science ®Google Scholar

Wang Y, Wang MD, Xia YP, et al. MicroRNA-130a regulates cerebral ischemia-induced blood-brain barrier permeability by targeting Homeobox A5. FASEB J. 2018;32:935–944.

 PubMed Web of Science ®Google Scholar

Fang Z, He QW, Li Q, et al. MicroRNA-150 regulates blood-brain barrier permeability via Tie-2 after permanent middle cerebral artery occlusion in rats. FASEB J. 2016;30:2097–2107.

 PubMed Web of Science ®Google Scholar

Ma F, Sun P, Zhang X, et al. Endothelium-targeted deletion of the miR-15a/16-1 cluster ameliorates blood-brain barrier dysfunction in ischemic stroke. Sci Signal. 2020;13:eaay5686.

 PubMed Web of Science ®Google Scholar

Xi T, Jin F, Zhu Y, et al. MicroRNA-126-3p attenuates blood-brain barrier disruption, cerebral edema and neuronal injury following intracerebral hemorrhage by regulating PIK3R2 and Akt. Biochem Biophys Res Commun. 2017;494:144–151.

 PubMed Web of Science ®Google Scholar

Xi T, Jin F, Zhu Y, et al. MiR-27a-3p protects against blood-brain barrier disruption and brain injury after intracerebral hemorrhage by targeting endothelial aquaporin-11. J Biol Chem. 2018;293:20041–20050.

 PubMed Web of Science ®Google Scholar

Burek M, Konig A, Lang M, et al. Hypoxia-induced microRNA-212/132 alter blood-brain barrier integrity through inhibition of tight junction-associated proteins in human and mouse brain microvascular endothelial cells. Transl Stroke Res. 2019;10:672–683.

 PubMed Web of Science ®Google Scholar

Ge X, Han Z, Chen F, et al. MiR-21 alleviates secondary blood-brain barrier damage after traumatic brain injury in rats. Brain Res. 2015;1603:150–157.

 PubMed Web of Science ®Google Scholar

Lopez-Ramirez MA, Wu D, Pryce G, Simpson JE, Reijerkerk A, King-Robson J, et al. MicroRNA-155 negatively affects blood-brain barrier function during neuroinflammation. FASEB J. 2014;28:2551–2565.

 PubMed Web of Science ®Google Scholar

Reijerkerk A, Lopez-Ramirez MA, van Het Hof B, et al. MicroRNAs regulate human brain endothelial cell-barrier function in inflammation: implications for multiple sclerosis. J Neurosci. 2013;33(16):6857–6863. .

 PubMed Web of Science ®Google Scholar

Rom S, Dykstra H, Zuluaga-Ramirez V, et al. MiR-98 and let-7g* protect the blood-brain barrier under neuroinflammatory conditions. J Cereb Blood Flow Metab. 2015;35:1957–1965.

 PubMed Web of Science ®Google Scholar

Song J, Hu Y, Li H, et al. MiR-1303 regulates BBB permeability and promotes CNS lesions following CA16 infections by directly targeting MMP9. Emerg Microbes Infect. 2018;7:155.

 PubMed Web of Science ®Google Scholar

Mishra R, Singh SK. HIV-1 Tat C modulates expression of miRNA-101 to suppress VE-cadherin in human brain microvascular endothelial cells. J Neurosci. 2013;33:5992–6000.

 PubMed Web of Science ®Google Scholar

Barker KR, Lu Z, Kim H, et al. MiR-155 modifies inflammation, endothelial activation and blood-brain barrier dysfunction in cerebral malaria. Mol Med. 2017;23:24–33.

 PubMed Web of Science ®Google Scholar

Liu W, Cai H, Lin M, et al. MicroRNA-107 prevents amyloid-beta induced blood-brain barrier disruption and endothelial cell dysfunction by targeting Endophilin-1. Exp Cell Res. 2016;343:248–257.

 PubMed Web of Science ®Google Scholar

Lin M, Zhu L, Wang J, et al. MiR-424-5p maybe regulate blood-brain barrier permeability in a model in vitro with Abeta incubated endothelial cells. Biochem Biophys Res Commun. 2019;517:525–531.

 PubMed Web of Science ®Google Scholar

Toyama K, Spin JM, Deng AC, et al. MicroRNA-mediated therapy modulating blood-brain barrier disruption improves vascular cognitive impairment. Arterioscler Thromb Vasc Biol. 2018;38:1392–1406.

 PubMed Web of Science ®Google Scholar

Song J, Yoon SR, Kim OY. MiR-Let7a controls the cell death and tight junction density of brain endothelial cells under high glucose condition. Oxid Med Cell Longev. 2017;2017:6051874.

 PubMed Web of Science ®Google Scholar

Yang MC, You FL, Wang Z, et al. Salvianolic acid B improves the disruption of high glucose-mediated brain microvascular endothelial cells via the ROS/HIF-1alpha/VEGF and miR-200b/VEGF signaling pathways. Neurosci Lett. 2016;630:233–240.

 PubMed Web of Science ®Google Scholar

Kalani A, Kamat PK, Familtseva A, et al. Role of microRNA29b in blood-brain barrier dysfunction during hyperhomocysteinemia: an epigenetic mechanism. J Cereb Blood Flow Metab. 2014;34:1212–1222.

 PubMed Web of Science ®Google Scholar

Bai Y, Zhang Y, Hua J, et al. Silencing microRNA-143 protects the integrity of the blood-brain barrier: implications for methamphetamine abuse. Sci Rep. 2016;6:35642.

 PubMed Web of Science ®Google Scholar

Tominaga N, Kosaka N, Ono M, et al. Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood-brain barrier. Nat Commun. 2015;6:6716.

 PubMed Web of Science ®Google Scholar

Zhu L, Lin M, Ma J, et al. The role of LINC00094/miR-224-5p (miR-497-5p)/Endophilin-1 axis in memantine mediated protective effects on blood-brain barrier in AD microenvironment. J Cell Mol Med. 2019;23:3280–3292.

 PubMed Web of Science ®Google Scholar

Ren L, Wei C, Li K, et al. LncRNA MALAT1 up-regulates VEGF-A and ANGPT2 to promote angiogenesis in brain microvascular endothelial cells against oxygen-glucose deprivation via targetting miR-145. Biosci Rep. 2019;39:BSR20180226.

 PubMed Web of Science ®Google Scholar

Zhang L, Luo X, Chen F, et al. LncRNA SNHG1 regulates cerebrovascular pathologies as a competing endogenous RNA through HIF-1alpha/VEGF signaling in ischemic stroke. J Cell Biochem. 2018;119:5460–5472.

 PubMed Web of Science ®Google Scholar

Zhang J, Dong B, Hao J, et al. LncRNA Snhg3 contributes to dysfunction of cerebral microvascular cells in intracerebral hemorrhage rats by activating the TWEAK/Fn14/STAT3 pathway. Life Sci. 2019;237:116929.

 PubMed Web of Science ®Google Scholar

Wu L, Ye Z, Pan Y, et al. Vascular endothelial growth factor aggravates cerebral ischemia and reperfusion-induced blood-brain-barrier disruption through regulating LOC102640519/HOXC13/ZO-1 signaling. Exp Cell Res. 2018;369:275–283.

 PubMed Web of Science ®Google Scholar

Leng X, Ma J, Liu Y, et al. Mechanism of piR-DQ590027/MIR17HG regulating the permeability of glioma conditioned normal BBB. J Exp Clin Cancer Res. 2018;37:246.

 PubMed Web of Science ®Google Scholar

Ma J, Wang P, Yao Y, et al. Knockdown of long non-coding RNA MALAT1 increases the blood-tumor barrier permeability by up-regulating miR-140. Biochim Biophys Acta. 2016;1859:324–338.

 PubMed Web of Science ®Google Scholar

Guo J, Cai H, Zheng J, et al. Long non-coding RNA NEAT1 regulates permeability of the blood-tumor barrier via miR-181d-5p-mediated expression changes in ZO-1, Occludin, and claudin-5. Biochim Biophys Acta Mol Basis Dis. 2017;1863:2240–2254.

 PubMed Web of Science ®Google Scholar

Guo J, Shen S, Liu X, et al. Role of linc00174/miR-138-5p (miR-150-5p)/FOSL2 feedback loop on regulating the blood-tumor barrier permeability. Mol Ther Nucleic Acids. 2019;18:1072–1090.

 PubMedGoogle Scholar

Cai H, Xue Y, Wang P, et al. The long non-coding RNA TUG1 regulates blood-tumor barrier permeability by targeting miR-144. Oncotarget. 2015;6:19759–19779.

 PubMedGoogle Scholar

Wu P, Gao Y, Shen S, et al. KHDRBS3 regulates the permeability of blood–tumor barrier via cDENND4C/miR-577 axis. Cell Death Dis. 2019;10(7):536. .

 PubMedGoogle Scholar

Yang L, Han B, Zhang Y, et al. Engagement of circular RNA HECW2 in the nonautophagic role of ATG5 implicated in the endothelial-mesenchymal transition. Autophagy. 2018;14(3):404–418. .

 PubMed Web of Science ®Google Scholar

Bai Y, Zhang Y, Han B, et al. Circular RNA DLGAP4 ameliorates ischemic stroke outcomes by targeting miR-143 to regulate endothelial-mesenchymal transition associated with blood–brain barrier integrity. J Neurosci. 2018;38(1):32–50. .

 PubMed Web of Science ®Google Scholar

Yang R, Chen J, Xu B, et al. Circ_2858 helps blood-brain barrier disruption by increasing VEGFA via sponging miR-93-5p during Escherichia coli meningitis. Mol Ther Nucleic Acids. 2020;22:708–721.

 PubMedGoogle Scholar