Novel Pathological Role of hnRNPA1 (Heterogeneous Nuclear Ribonucleoprotein A1) in Vascular Smooth Muscle Cell Function and Neointima Hyperplasia

Zhang, Li; Chen, Qishan; An, Weiwei; Yang, Feng; Maguire, Eithne Margaret; Chen, Dan; Zhang, Cheng; Wen, Guangwu; Yang, Mei; Dai, Bin; Luong, Le Anh; Zhu, Jiang; Xu, Qingbo; Xiao, Qingzhong

doi:10.1161/atvbaha.117.310020

Cited by 47 publications

(45 citation statements)

References 52 publications

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“…Real‐time quantitative polymerase chain reaction was performed as previously described 17, 18, 19, 27, 28, 29, 30, 31. Briefly, total RNA was extracted from murine aortas or cells using Trizol reagent (Sigma) according to the manufacturer's instructions and subjected to DNase I (Sigma) digestion to remove potential DNA contamination.…”

Section: Methodsmentioning

confidence: 99%

“…Immunofluorescent assay was performed as previously described. 13,14,[17][18][19] Briefly, frozen tissue sections were labeled with appropriate isotype IgG control or antibodies as indicated in the figures and visualized with appropriate secondary antibodies conjugated with CF 488A or CF 568 (Sigma) for the unconjugated primary antibodies. Sections were counterstained with 4 0 ,6-diamidino-2-phenylindole (DAPI; Sigma).…”

Section: Immunofluorescent Staining Of the Frozen Tissue Sectionsmentioning

confidence: 99%

“…Real-time quantitative polymerase chain reaction was performed as previously described. [17][18][19][27][28][29][30][31] Briefly, total RNA was extracted from murine aortas or cells using Trizol reagent (Sigma) according to the manufacturer's instructions and subjected to DNase I (Sigma) digestion to remove potential DNA contamination. Reverse transcription for long RNAs was performed using an Improm-II Reverse Transciption Kit Eight-week-old male Apolipoprotein E (ApoE) knockout (ApoE À/À ) mice were fed a high-fat diet (HFD) for 6, 8, 12, or 24 weeks, respectively.…”

Section: Real-time Quantitative Polymerase Chain Reactionmentioning

confidence: 99%

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Genetic and Pharmacologic Inhibition of the Neutrophil Elastase Inhibits Experimental Atherosclerosis

Wen

Chen

et al. 2018

JAHA

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BackgroundTo investigate whether neutrophil elastase (NE) plays a causal role in atherosclerosis, and the molecular mechanisms involved.Methods and Results NE genetic–deficient mice (Apolipoprotein E−/−/NE −/− mice), bone marrow transplantation, and a specific NE inhibitor (GW311616A) were employed in this study to establish the causal role of NE in atherosclerosis. Aortic expression of NE mRNA and plasma NE activity was significantly increased in high‐fat diet (HFD)–fed wild‐type (WT) (Apolipoprotein E−/−) mice but, as expected, not in NE‐deficient mice. Selective NE knockout markedly reduced HFD‐induced atherosclerosis and significantly increased indicators of atherosclerotic plaque stability. While plasma lipid profiles were not affected by NE deficiency, decreased levels of circulating proinflammatory cytokines and inflammatory monocytes (Ly6Chi/CD11b+) were observed in NE‐deficient mice fed with an HFD for 12 weeks as compared with WT. Bone marrow reconstitution of WT mice with NE −/− bone marrow cells significantly reduced HFD‐induced atherosclerosis, while bone marrow reconstitution of NE −/− mice with WT bone marrow cells restored the pathological features of atherosclerotic plaques induced by HFD in NE‐deficient mice. In line with these findings, pharmacological inhibition of NE in WT mice through oral administration of NE inhibitor GW311616A also significantly reduced atherosclerosis. Mechanistically, we demonstrated that NE promotes foam cell formation by increasing ATP‐binding cassette transporter ABCA1 protein degradation and inhibiting macrophage cholesterol efflux.ConclusionsWe outlined a pathogenic role for NE in foam cell formation and atherosclerosis development. Consequently, inhibition of NE may represent a potential therapeutic approach to treating cardiovascular disease.

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Section: Methodsmentioning

confidence: 99%

Section: Immunofluorescent Staining Of the Frozen Tissue Sectionsmentioning

confidence: 99%

Section: Real-time Quantitative Polymerase Chain Reactionmentioning

confidence: 99%

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Genetic and Pharmacologic Inhibition of the Neutrophil Elastase Inhibits Experimental Atherosclerosis

Wen

Chen

et al. 2018

JAHA

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“…Functions of various hnRNPs range from transcriptional regulation to post-transcriptional processing, transport, spatial localization and degradation of different RNAs in a tissue and transcript-specific manner (Appocher et al 2017; Chaudhury et al 2010; Coyne et al 2015; Estes et al 2008; Han et al 2010; Piccolo et al 2014; Romano et al 2016; Specchia et al 2017; Zhang et al 2017). Since the levels of transcripts encoding most of the hnRNPs and other omega speckle associated RBPs were not found to be altered in hsrω 66 or Hsp90GFP or hsrω 66 Hsp90GFP homozygotes, the observed effects on expression of various genes in genotypes with reduced levels of hsrω transcripts are likely to be consequences of the altered dynamics and spatial distribution of the omega speckle associated hnRNPs and other proteins.…”

Section: Discussionmentioning

confidence: 99%

Over-expression of Hsp83 in grossly depletedhsrωlncRNA background causes synthetic lethality andl(2)glphenocopy inDrosophila

Ray

Acharya

Shambhavi

et al. 2018

Preprint

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We examined interactions between Hsp83 and hsrω lncRNAs in hsrω 66 Hsp90GFP homozygotes, which almost completely lack hsrω lncRNAs but over-express Hsp83. All +/+; hsrω 66 Hsp90GFP progeny died before third instar. Rare Sp/CyO; hsrω 66 Hsp90GFP reached third instar stage but phenocopied l(2)gl mutants, dying after prolonged larval life, becoming progressively bulbous and transparent with enlarged brain. Additionally, ventral ganglia were elongated. However, hsrω 66 Hsp90GFP/TM6B heterozygotes, carrying +/+ or Sp/CyO second chromosomes, developed normally. Total RNA sequencing (+/+, +/+; hsrω 66 /hsrω 66 , Sp/CyO; hsrω 66 /hsrω 66 , +/+; Hsp90GFP/Hsp90GFP, and Sp/CyO; hsrω 66 Hsp90GFP/hsrω 66 Hsp90GFP late third instar larvae) revealed similar effects on many genes in hsrω 66 and Hsp90GFP homozygotes. Besides additive effect on many of them, numerous additional genes were affected in Sp/CyO; hsrω 66 Hsp90GFP larvae, with l(2)gl and several genes regulating CNS being highly down-regulated in surviving Sp/CyO; hsrω 66 Hsp90GFP larvae, but not in hsrω 66 or Hsp90GFP single mutants. Hsp83 binds at these gene promoters. Several omega speckle associated hnRNPs too may bind with these genes and transcripts. Hsp83-hnRNP interactions are also known. Thus, elevated Hsp83 in altered hnRNP distribution and dynamics, following absence of hsrω lncRNAs and omega speckles, background can severely perturb regulatory circuits with unexpected consequences, including down-regulation of tumor suppressor gene like l(2)gl. 0 1 5

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“…Transient-transfection and luciferase assays. Luciferase assays for the miR-486 promoter or Mmp2 3=UTR reporters were conducted as in previous studies (26,29,(62)(63)(64)(65). Briefly, for gene promoter activity assays, SSCs were cotransfected with vectors expressing individual miR-486 promoters (pGL3-miR-486__1080 bp, _Intron, _1080 bp-Distal, _1080 bp-Middle, and _1080 bp-Proximal; 0.15 g/2.5 ϫ 10 4 cells) and pRenilla (15 ng/2.5 ϫ 10 4 cells) using Lipofectamine 2000 according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

A Novel Regulatory Axis, CHD1L-MicroRNA 486-Matrix Metalloproteinase 2, Controls Spermatogonial Stem Cell Properties

Liu

Maguire

Bai

et al. 2019

Molecular and Cellular Biology

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Spermatogonial stem cells (SSCs) are unipotent germ cells that are at the foundation of spermatogenesis and male fertility. However, the underlying molecular mechanisms governing SSC stemness and growth properties remain elusive. We have recently identified chromodomain helicase/ATPase DNA binding protein 1-like (Chd1l) as a novel regulator for SSC survival and self-renewal, but how these functions are controlled by Chd1l remains to be resolved. Here, we applied high-throughput small RNA sequencing to uncover the microRNA (miRNA) expression profiles controlled by Chd1l and showed that the expression levels of 124 miRNA transcripts were differentially regulated by Chd1l in SSCs. KEGG pathway analysis shows that the miRNAs that are differentially expressed upon Chd1l repression are significantly enriched in the pathways associated with stem cell pluripotency and proliferation. As a proof of concept, we demonstrate that one of the most highly upregulated miRNAs, miR-486, controls SSC stemness gene expression and growth properties. The matrix metalloproteinase 2 (MMP2) gene has been identified as a novel miR-486 target gene in the context of SSC stemness gene regulation and growth properties. Data from cotransfection experiments showed that Chd1l, miR-486, and MMP2 work in concert in regulating SSC stemness gene expression and growth properties. Finally, our data also revealed that MMP2 regulates SSC stemness gene expression and growth properties through activating β-catenin signaling by cleaving N-cadherin and increasing β-catenin nuclear translocation. Our data demonstrate that Chd1l–miR-486–MMP2 is a novel regulatory axis governing SSC stemness gene expression and growth properties, offering a novel therapeutic opportunity for treating male infertility.

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Novel Pathological Role of hnRNPA1 (Heterogeneous Nuclear Ribonucleoprotein A1) in Vascular Smooth Muscle Cell Function and Neointima Hyperplasia

Abstract: Supplemental Digital Content is available in the text.

Cited by 47 publications

References 52 publications

Genetic and Pharmacologic Inhibition of the Neutrophil Elastase Inhibits Experimental Atherosclerosis

Genetic and Pharmacologic Inhibition of the Neutrophil Elastase Inhibits Experimental Atherosclerosis

Over-expression of Hsp83 in grossly depletedhsrωlncRNA background causes synthetic lethality andl(2)glphenocopy inDrosophila

A Novel Regulatory Axis, CHD1L-MicroRNA 486-Matrix Metalloproteinase 2, Controls Spermatogonial Stem Cell Properties

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