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Long non-coding RNA MALAT1 regulates angiogenesis following oxygen-glucose deprivation/reoxygenation.

ABSTRACT: Long non-coding RNAs (lncRNAs) have been identified as playing critical roles in multiple diseases. However, little is known regarding their roles and mechanisms in post-stroke angiogenesis. Our studies focused on deciphering the functional roles and the underlying mechanisms of the lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in the process of angiogenesis following oxygen-glucose deprivation/reoxygenation (OGD/R). We characterized the up-regulation of MALAT1 expression in the process of angiogenesis after hypoxic injury in vivo and in vitro. We further showed that compared with the empty vector, MALAT1 knockdown had significantly reduced the capacity for angiogenesis, which was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT), scratching, cell cycle and immunofluorescent staining. Thus, our findings suggest that MALAT1 may mediate proangiogenic function in OGD/R. To further explore the potential mechanisms, we used lentiviruses expressing shMALAT1 and empty vector; the results revealed that shMALAT1 reduced the expression of 15-lipoxygenase 1 (15-LOX1), vascular endothelial growth factor (VEGF) and the phosphorylation of signal transducers and activators of transcription 3 (pSTAT3). Taken together, our results are the first to propose that MALAT1 may regulate angiogenesis through the 15-LOX1/STAT3 signalling pathway, and they may provide a critical target for the treatment of hypoxic injury and an avenue for therapeutic angiogenesis.

SUBMITTER: Wang C

PROVIDER: S-EPMC6433728 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Long non-coding RNA MALAT1 regulates angiogenesis following oxygen-glucose deprivation/reoxygenation.

Wang Chengya C Qu Youyang Y Suo Rui R Zhu Yulan Y

Journal of cellular and molecular medicine 20190219 4

Long non-coding RNAs (lncRNAs) have been identified as playing critical roles in multiple diseases. However, little is known regarding their roles and mechanisms in post-stroke angiogenesis. Our studies focused on deciphering the functional roles and the underlying mechanisms of the lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in the process of angiogenesis following oxygen-glucose deprivation/reoxygenation (OGD/R). We characterized the up-regulation of MALAT1 expressio ...[more]

PMID: 30784209

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Project description:N1-Methyladenosine (m1A) is an abundant modification of transcripts, plays important roles in regulating mRNA structure and translation efficiency, and is dynamically regulated under stress. However, the characteristics and functions of mRNA m1A modification in primary neurons and oxygen glucose deprivation/reoxygenation (OGD/R) induced remain unclear. We first constructed a mouse cortical neuron OGD/R model and then used methylated RNA immunoprecipitation (MeRIP) and sequencing technology to demonstrate that m1A modification is abundant in neuron mRNAs and dynamically regulated during OGD/R induction. Our study suggests that Trmt10c, Alkbh3, and Ythdf3 may be m1A-regulating enzymes in neurons during OGD/R induction. The level and pattern of m1A modification change significantly during OGD/R induction, and differential methylation is closely associated with the nervous system. Our findings show that m1A peaks in cortical neurons aggregate at both the 5' and 3' untranslated regions. m1A modification can regulate gene expression, and peaks in different regions have different effects on gene expression. By analysing m1A-seq and RNA-seq data, we show a positive correlation between differentially methylated m1A peaks and gene expression. The correlation was verified by using qRT-PCR and MeRIP-RT-PCR. Moreover, we selected human tissue samples from Parkinson's disease (PD) and Alzheimer's disease (AD) patients from the Gene Expression Comprehensive (GEO) database to analyse the selected differentially expressed genes (DEGs) and differential methylation modification regulatory enzymes, respectively, and found similar differential expression results. We highlight the potential relationship between m1A modification and neuronal apoptosis following OGD/R induction. Furthermore, by mapping mouse cortical neurons and OGD/R-induced modification characteristics, we reveal the important role of m1A modification in OGD/R and gene expression regulation, providing new ideas for research on neurological damage.

Project description:Cerebral endothelial cells play an essential role in brain angiogenesis, and their function has been found to be impaired in diabetes. Methylglyoxal (MG) is a highly reactive dicarbonyl metabolite of glucose formed mainly during glycolysis, and its levels can be elevated in hyperglycemic conditions. MG is a potent precursor of AGEs (advanced glycation end-products). In this study, we investigated if MG can induce angiogenesis dysfunction and whether MG scavengers can ameliorate angiogenesis dysfunction induced by MG. Here, we used cultured human brain microvascular endothelial cells (HBMECs) treated with MG and oxygen-glucose deprivation (OGD) to mimic diabetic stroke in vitro. We also used the MG challenged chicken embryo chorioallantoic membrane (CAM) to study angiogenesis in vivo. Interestingly, administration of MG significantly impaired cell proliferation, cell migration, and tube formation and decreased protein expression of angiogenesis-related factors, which was rescued by three different MG scavengers, glyoxalase 1 (GLO1), aminoguanidine (AG), and N-acetyl cysteine (NAC). In cultured CAM, MG exposure significantly reduced angiogenesis and the angiogenesis-related dysfunction could be attenuated by pretreatment with AG or NAC. Treatment of cultured HBMECs with MG plus OGD increased cellular apoptosis significantly, which could be prevented by exposure to GLO1, AG, or NAC. We also noted that administration of MG increased cellular oxidative stress as measured by reactive oxygen species (ROS) generation, enhanced AGE accumulation, and receptor for advanced glycation end-product (RAGE) expression in the cultured HBMECs, which were partially reversed by GLO1, AG, or NAC. Taken together, our findings demonstrated that GLO1, AG, or NAC administration can ameliorate MG-induced angiogenesis dysfunction, and this can be mainly attributed to attenuated ROS production, reduced cellular apoptosis, and increased levels of angiogenic factors. Overall, this study suggested that GLO1, AG, or NAC may be promising candidate compounds for the treatment of angiogenesis dysfunction caused by hyperglycemia in diabetic ischemic stroke.

Dataset Information

Long non-coding RNA MALAT1 regulates angiogenesis following oxygen-glucose deprivation/reoxygenation.

Publications

Long non-coding RNA MALAT1 regulates angiogenesis following oxygen-glucose deprivation/reoxygenation.

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