LncRNA MALAT1 improves cerebral ischemia-reperfusion injury and cognitive dysfunction by regulating miR-142-3p/SIRT1 axis

Abstract

Purpose:

To investigate the regulation and related mechanisms of MALAT1 in cerebral ischemia- reperfusion (CI/R) injury.

Materials and methods:

72 mice were divided into sham group (n=24), MCAO group (n=24), MCAO+pcDNA-NC group (n=12) and MCAO+MALAT1 group (n=12). At 12 h, 24 h and 48 h after reperfusion, 6 mice were randomly selected from the sham group and the MCAO group to detect the expression of MALAT1, miR-142-3p and SIRT1 in brain tissue. All mice were scored for neurobehavioral after 48 h of reperfusion. After the completion of the scoring, 6 mice were randomly selected from each group and brain tissue was obtained for TTC analysis. The remaining mice of each group were kept on the Morris water maze test after 3 days of feeding. TTC staining and cerebral infarct volume determination. The infarct size of each brain slice was calculated using Image J image analysis software. OGD/R model PC12 cells were prepared according to simulating CI/R injury in vitro. MALAT1 was cloned into the pcDNA3.1 to construct a MALAT1 overexpression vector with the empty vector NC as a control. Plasmid or oligonuceotides were transfected into PC12 cells. The content of TNF-α, IL-1β, IL-6, the content of reactive oxygen species (ROS), malondialdehyde (MDA) in brain tissue was detected. The activity of superoxide dismutase (SOD), catalase (CAT) activity was measured.

Results:

MALAT1 was down-regulated in a time-dependent manner in CI/R-damaged mouse cerebral cortex and OGD/R-induced PC12 cells, accompanied by an increase in the expression of miR-142-3p and a decrease in sirtuin 1 (SIRT1) expression. Overexpression of MALAT1 inhibited OGD/R-induced cell necrosis and apoptosis and promoted cell proliferation. Overexpression of MALAT1 reduced the levels of TNF-α, IL-6, IL-1β, ROS and MDA and increased the activities of SOD and CAT in OGD/R-injured PC12 cells. MALAT1 negatively regulated the expression of miR-142-3p, and SIRT1 was a target gene of miR-142-3p. The expression of SIRT1 induced by MALAT1 overexpression was obviously abolished by the introduction of miR-142-3p mimic. MALAT1 overexpression can exert its role by regulating the miR-142-3p/SIRT1 axis. Besides, overexpression of MALAT1 improved cerebral infarction, neurological impairment and cognitive dysfunction in CI/R mice.

Conclusion:

MALAT1 mediates SIRT1 expression by acting as a ceRNA of miR-142-3p to improve CI/R injury.

Abbreviations: CAT: catalase; CI/R: cerebral ischemia-reperfusion; IL-1β: interleukin-1β; IL-6: interleukin-6; lncRNA: long-chain non-coding RNA; MALAT1: metastasis-associated lung adenocarcinoma transcript1; MCAO: middle cerebral artery occlusion; MDA: malondialdehyde; OGD/R: oxygen-glucose deprivation and reoxygenation; ROS: reactive oxygen species; SIRT1: sirtuin 1; SOD: superoxide dismutase; TNF-α: tumour necrosis factor-alpha

Keywords:

• Cerebral ischemia-reperfusion injury
• oxygen-glucose deprivation/reoxygenation
• lncRNA MALAT1
• miR-142-3p/SIRT1 axis

Author contributions

S.X.M. designed the study, conducted most of the experiments and wrote the manuscript; B.W. and W.T.L. conducted the experiments and analyzed the data. All authors have read and approved the manuscript.

Ethics approval and consent to participate

The present study was approved by the Ethic Committee and Animal Center of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital.

Consent for publication

All authors agreed the submission and the policy of the journal and copyright.

Disclosure statement

No potential conflict of interest was reported by the authors.

Availability of data and material

All data in this study can be obtained by proper request from the authors.

Abbreviations

Additional information

Funding

The authors were supported financially by (1) Project of Shanghai science and technology commission [19401932500]; (2) Shanghai municipal government will further accelerate the three-year action plan for the development of TCM (2018-2020) for major clinical research on TCM [ZY (2018-2020)-cccx-4010]; (3) Innovation fund of integrated traditional Chinese and western medicine, school of medicine, Shanghai Jiao Tong university [18zxy002]; and (4) 2019 Teacher Training and Development Project of Medical School of Shanghai Jiao Tong University [JFXM201909].