The Role Of MiR-143 In Blood-brain Barrier And Its Regulation Mechanisms

Part I The role of miR-143 in blood-brain barrier: Implication for methamphetamine abuse Objective: Most of the central nervous system diseases are accompanied by severe neuroinflammatory responses.Early studies show that neuroinflammatory responses play an important role in the pathological process in the brain.Blood brain barrier(BBB)damage is an important event of neuroinflammatory reaction induced by methamphetamine.MicroRNA-143(miR-143)plays a critical role in various cellular processes;however,the role of miR-143 in the maintenance of blood-brain barrier(BBB)integrity remains poorly defined.Methods and results: Silencing miR-143 in a genetic animal model or via an Anti-miR-143 lentivirus ameliorated the BBB damage induced by methamphetamine.MiR-143,targeting p53 unregulated modulator of apoptosis(PUMA),increased the permeability of human brain endothelial cells and concomitantly decreased the expression of tight junction proteins(TJPs).Silencing miR-143 increased the expression of TJPs and protected the integrity of BBB against methamphetamine treatment.Overexpression of PUMA increased the expression of TJPs through a mechanism that involved the NF-kB and p53 transcription factor pathways.Mechanically,methamphetamine mediated up-regulation of miR-143 via sigma-1 receptor with sequential activation of mitogen-activated protein kinases(MAPKs)and phosphatidylinositol-3' kinase(PI3K)/Akt and STAT3 pathways.Conclusion: Silencing miR-143 could provide a novel therapeutic strategy for BBB damage-related vascular dysfunction.Part II Silencing micro RNA-143 ameliorates stroke outcomes to regulate endothelial-mesenchymal transition associated with blood-brain barrierObjective: Cerebral apoplexy is an acute cerebrovascular disease characterized by focal loss of nerve function.BBB damage is one of the important initiating factor of cerebral stroke,and mi R-143 is involved in regulating the function of blood brain barrier,circ DLGAP4 transcripts and mi R-143 binding sites,circ DLGAP4 targeting mi R-143 regulation mechanism of brain injury of stroke BBB molecules.Circular RNAs(circ RNAs)are highly expressed in the central nervous system and regulate physiological and pathophysiological processes.However,the potential role of circ RNAs in stroke remains largely unknown.Methods and results: Here,we show that the circular RNA DLGAP4(circ DLGAP4)functions as an endogenous micro RNA-143(mi R-143)sponge to inhibit mi R-143 activity,resulting in the inhibition of HECT domain E3 ubiquitin protein ligase 1(HECTD1)expression.Circ DLGAP4 levels were significantly decreased in the plasma of acute ischemic stroke patients(13 females and 13 males)and in a mouse stroke model.Upregulation of circ DLGAP4 expression significantly attenuated neurological deficits and decreased infarct areas and blood-brain barrier(BBB)damage in the t MCAO(transient middle cerebral artery occlusion)mouse stroke model.Endothelial-mesenchymal transition(Endo MT)contributes to BBB disruption and circ DLGAP4 overexpression significantly inhibited Endo MT by regulating tight junction protein(TJP)and mesenchymal cell marker expression.Conclusion: The results of our study are illustrative of the involvement of mi R-143 and circ DLGAP4 and its mechanism in cerebral ischemia,providing translational evidence that they serve as novel therapeutic targets for acute cerebrovascular protection.