Ca2+-activated Cl− channel TMEM16A inhibition by cholesterol promotes angiogenesis in endothelial cells

Ma, Ke; Liu, Sitong; Liang, Hongyue; Wang, Guan; Wang, Tianyu; Luo, Shuya; Gao, Kuan; Wang, Hui; Liu, Mei; Bai, Lichuan; Xiao, Qinghuan

doi:10.1016/j.jare.2020.09.003

Cited by 11 publications

(10 citation statements)

References 37 publications

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“…Inhibiting ANO1 significantly rescued OGD/R-induced downregulation of TJ proteins and upregulation of BBB permeability in vitro ( Liu et al, 2019 ). And the present studies showed that ANO1 affects the functions of brain capillary endothelial cells, which are involved in BBB functions ( Suzuki et al, 2020 ; Liu et al, 2021 ; Ma et al, 2021 ; Suzuki et al, 2021 ).…”

Section: Introductionsupporting

confidence: 55%

The Novel lncRNA ENST00000530525 Affects ANO1, Contributing to Blood–Brain Barrier Injury in Cultured hCMEC/D3 Cells Under OGD/R Conditions

Jiang

Cai

et al. 2022

Front. Genet.

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Ischemic stroke (IS) is a major neurological disease with high fatality and residual disability burdens. Long noncoding RNAs (lncRNAs) have been found to play an important role in IS. However, the roles and significance of most lncRNAs in IS are still unknown. This study was performed to identify differentially expressed (DE) lncRNAs using a lncRNA microarray in whole blood samples of patients suffering from acute cerebral ischemia. Bioinformatics analyses, including GO, KEGG pathway enrichment analysis, and proximity to putative stroke risk location analysis were performed. The novel lncRNA, ENST00000530525, significantly decreased after IS. Furthermore, we evaluated lncRNA ENST00000530525 expression in cultured hCMEC/D3 cells under oxygen-glucose deprivation/reoxygenation (OGD/R) conditions using fluorescent in situ hybridization (FISH) and quantitative real-time polymerase chain reaction (RT–qPCR) analysis. To investigate the function of lncRNA ENST00000530525, its over-expression (OE) and negative control (NC) plasmids were transfected into hCMEC/D3 cells, and cell viability was detected by a cell counting kit-8 (CCK-8) assay after OGD/R. LncRNA ENST00000530525 and ANO1 expression were investigated using RT–qPCR and immunofluorescence. For blood–brain barrier (BBB) permeability, FITC-dextran transendothelial permeability assay and tight junction (TJ) protein immunofluorescence assays were performed. There were 3352 DE lncRNAs in the blood samples of acute IS patients. The validation results were consistent with the gene chip data. The GO and KEGG results showed that these lncRNAs were mainly related to oxygen and glucose metabolism, leukocyte transendothelial migration, mitophagy and cellular senescence. Among these, lncRNA ENST00000530525 was the most highly downregulated lncRNA and it was mapped within the IS-associated gene anoctamin-1 (ANO1). We further found that lncRNA ENST00000530525 was downregulated in hCMEC/D3 cells under 4 h OGD and 20 h reoxygenation (OGD4/R20) conditions. Upregulating lncRNA ENST00000530525 by plasmid transfection decreased cell viability while increasing ANO1 expression and it contributed to BBB injury in hCMEC/D3 cells after OGD4/R20. The lncRNA ENST00000530525 might play deleterious roles in post-stroke pathogenesis. These results show that some DE lncRNAs in humans participate through characteristic roles in post-stroke pathogenesis; thus, the roles and significance of some novel lncRNAs in IS warrant further study.

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Section: Introductionsupporting

confidence: 55%

The Novel lncRNA ENST00000530525 Affects ANO1, Contributing to Blood–Brain Barrier Injury in Cultured hCMEC/D3 Cells Under OGD/R Conditions

Jiang

Cai

et al. 2022

Front. Genet.

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“…Firstly, the Student’s t-test, non-parametric test, chi-square test, or one-way analysis was used to check whether there were significant differences on the demographic data among the three groups ( Ma et al., 2021 ). Secondly, the orthogonal partial least-square discriminant analysis (OPLS-DA) was used to identify the differential genera responsible for the discrimination between MDD patients and HC.…”

Section: Methodsmentioning

confidence: 99%

Differential Gut Microbiota Compositions Related With the Severity of Major Depressive Disorder

Zhong

Chen

Wang

et al. 2022

Front. Cell. Infect. Microbiol.

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ObjectiveIncreasing evidence shows a close relationship between gut microbiota and major depressive disorder (MDD), but the specific mechanisms remain unknown. This study was conducted to explore differential gut microbiota compositions related to the severity of MDD.MethodsHealthy controls (HC) (n = 131) and MDD patients (n = 130) were included. MDD patients with Hamilton Depression Rating Scale (HDRS) score <25 and ≥25 were assigned into moderate (n = 72) and severe (n = 58) MDD groups, respectively. Univariate and multivariate analyses were used to analyze the gut microbiota compositions at the genus level.ResultsThirty-six and 27 differential genera were identified in moderate and severe MDD patients, respectively. The differential genera in moderate and severe MDD patients mainly belonged to three (Firmicutes, Actinobacteriota, and Bacteroidota) and two phyla (Firmicutes and Bacteroidota), respectively. One specific covarying network from phylum Actinobacteriota was identified in moderate MDD patients. In addition, five genera (Collinsella, Eggerthella, Alistipes, Faecalibacterium, and Flavonifractor) from the shared differential genera by two MDD groups had a fair efficacy in diagnosing MDD from HC (AUC = 0.786).ConclusionsOur results were helpful for further exploring the role of gut microbiota in the pathogenesis of depression and developing objective diagnostic methods for MDD.

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“…In human aortic ECs, TMEM16A is a negative regulator of proliferation, migration and angiogenesis. TMEM16A inhibition by cholesterol contributes to endothelial dysfunction ( Ma et al, 2021 ). In HUVECs, TMEM16A is a positive regulator of reactive oxygen species generation, which induces endothelial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…Human umbilical vein endothelial cells (HUVECs) were commonly used for angiogenesis studies ( Nowak-Sliwinska et al, 2018 ). TMEM16A is expressed in several EC types and displays dissimilar even paradoxical functions ( Wu et al, 2014 ; Ma et al, 2017 ; Ayed et al, 2018 ; Liu et al, 2019 ; Suzuki et al, 2020 ; Ma et al, 2021 ). The relationship between TMEM16A and angiogenesis under stress is unknown.…”

Section: Introductionmentioning

confidence: 99%

TMEM16A Plays an Insignificant Role in Myocardium Remodeling but May Promote Angiogenesis of Heart During Pressure-overload

Zhang

Duan

et al. 2022

Front. Physiol.

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Background: Cardiac hypertrophy (CH) occurs with an increase in myocardium mass as an adaptive compensation to increased stress. Prolonged CH causes decompensated heart failure (HF). Enhanced angiogenesis by vascular endothelial growth factor (VEGF) is observed in hypertrophied hearts; impaired angiogenesis by angiotensin II (AngII) is observed in failing hearts. Angiogenesis is executed by vascular endothelial cells (ECs). Abnormal Ca2+ homeostasis is a hallmark feature of hypertrophied and failing hearts. Ca2+-activated chloride channel transmembrane protein 16A (TMEM16A) is expressed in cardiomyocytes and ECs but its role in heart under stress remains unknown.Methods: Pressure-overload-induced CH and HF mouse models were established. Echocardiography was performed to evaluate cardiac parameters. Quantitative real-time PCR, traditional and simple western assays were used to quantify molecular expression. Whole-cell patch-clamp experiments were used to detect TMEM16A current (ITMEM16A) and action potential duration (APD) of cardiomyocytes. VEGF and AngII were used separately in ECs culture to simulate enhanced or impaired angiogenesis, respectively. TMEM16A low-expressed and over-expressed ECs were obtained by siRNA or lentivirus transfection. Wound healing, tube formation and ECs spheroids sprouting assays were performed to assess migration and angiogenesis.Results: Neither TMEM16A molecular expression levels nor whole-cell ITMEM16A density varied significantly during the development of CH and HF. ITMEM16A comprises transient outward current, but doesn’t account for APD prolongation in hypertrophied or failing cardiomyocytes. In cultured ECs, TMEM16A knockdown inhibited migration and angiogenesis, TMEM16A overexpression showed opposite result. Promotion of migration and angiogenesis by VEGF was decreased in TMEM16A low-expressed ECs but was increased in TMEM16A over-expressed ECs. Inhibition of migration and angiogenesis by AngII was enhanced in TMEM16A low-expressed ECs but was attenuated in TMEM16A over-expressed ECs.Conclusion: TMEM16A contributes insignificantly in myocardium remodeling during pressure-overload. TMEM16A is a positive regulator of migration and angiogenesis under normal condition or simulated stress. TMEM16A may become a new target for upregulation of angiogenesis in ischemic disorders like ischemic heart disease.

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Ca2+-activated Cl− channel TMEM16A inhibition by cholesterol promotes angiogenesis in endothelial cells

Abstract: Graphical abstract Cholesterol reduces TMEM16A expression via DNMT1-mediated promoter methylation and directly inhibits channel activities. TMEM16A inhibition promotes endothelial angiogenesis.

Cited by 11 publications

References 37 publications

The Novel lncRNA ENST00000530525 Affects ANO1, Contributing to Blood–Brain Barrier Injury in Cultured hCMEC/D3 Cells Under OGD/R Conditions

The Novel lncRNA ENST00000530525 Affects ANO1, Contributing to Blood–Brain Barrier Injury in Cultured hCMEC/D3 Cells Under OGD/R Conditions

Differential Gut Microbiota Compositions Related With the Severity of Major Depressive Disorder

TMEM16A Plays an Insignificant Role in Myocardium Remodeling but May Promote Angiogenesis of Heart During Pressure-overload

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