MicroRNA-223 Attenuates Hypoxia-induced Vascular Remodeling by Targeting RhoB/MLC2 in Pulmonary Arterial Smooth Muscle Cells

Zeng, Yan; Zhang, Xiaoying; Kang, Kang; Chen, Jidong; Wu, Zhiqin; Huang, Jinyong; Lu, Wenju; Chen, Yuqin; Zhang, Jie; Wang, Zhiwei; Zhai, Yujia; Qu, Junle; Ramchandran, Ramaswamy; Raj, J. Usha; Wang, Jian; Gou, Deming

doi:10.1038/srep24900

Cited by 64 publications

(48 citation statements)

References 56 publications

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“…Ubiquitin‐mediated degradation was further ruled out by treatment with the proteasome inhibitor MG132 which did not rescue RhoB expression on gels (Figure c). In addition to proteasomal degradation, RhoB levels can be modulated by micro‐RNAs including miRs‐19a, ‐19b, ‐21, and ‐223 (Niu et al, ; Sabatel et al, ; Zeng et al, ). However, since our Myc‐tagged rhoB construct lacks the 3'‐UTR these miRNAs are unlikely to be responsible for RhoB downregulation on soft substrates.…”

Section: Resultsmentioning

confidence: 99%

Matrix stiffness regulates endosomal escape of uropathogenicE. coli

Moorthy

Byfield

Janmey

et al. 2020

Cellular Microbiology

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Uropathogenic E. coli (UPEC) infection in vivo is characterized by invasion of bladder umbrella epithelial cells followed by endosomal escape and proliferation in the cytoplasm to form intracellular bacterial communities. By contrast, UPEC infection in tissue culture models results in bacteria being trapped within Lamp1‐positive endosomes where proliferation is limited. Pharmacological disruption of the actin cytoskeleton has been shown to facilitate UPEC endosomal escape in vitro and extracellular matrix stiffness is a well‐characterized physiological regulator of actin dynamics; therefore, we hypothesized that substrate stiffness may play a role in UPEC endosomal escape. Using functionalized polyacrylamide substrates, we found that at physiological stiffness, UPEC escaped the endosome and proliferated rapidly in the cytoplasm of bladder epithelial cells. Dissection of the cytoskeletal signaling pathway demonstrated that inhibition of the Rho GTPase RhoB or its effector PRK1 was sufficient to increase cytoplasmic bacterial growth and that RhoB protein level was significantly reduced at physiological stiffness. Our data suggest that tissue stiffness is a critical regulator of intracellular bacterial growth. Due to the ease of doing genetic and pharmacological manipulations in cell culture, this model system may provide a useful tool for performing mechanistic studies on the intracellular life cycle of uropathogens.

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Section: Resultsmentioning

confidence: 99%

Matrix stiffness regulates endosomal escape of uropathogenicE. coli

Moorthy

Byfield

Janmey

et al. 2020

Cellular Microbiology

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“…Cell migration was determined by the wound‐healing assay, as reported previously . In brief, cells were maintained in starvation condition for 12 hours, then a line scratch was made in the cell layer and photographed immediately as initial image (0 hour).…”

Section: Methodsmentioning

confidence: 99%

“…Cell migration was determined by the wound-healing assay, as reported previously. 44 In brief, cells were maintained in starvation condition for 12 hours, then a line scratch was made in the cell layer and photographed immediately as initial image (0 hour). The second image (24 hours) of the same line scratch was taken after 24 hours of culturing, and cell migration was determined by measuring the decreased width of corresponding scratch from 0 to 24 hours.…”

Section: Cell Proliferation and Migration Assaysmentioning

confidence: 99%

Phosphatidylinositol 3‐Kinase–DNA Methyltransferase 1–miR‐1281–Histone Deacetylase 4 Regulatory Axis Mediates Platelet‐Derived Growth Factor–Induced Proliferation and Migration of Pulmonary Artery Smooth Muscle Cells

Qian

et al. 2018

JAHA

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BackgroundPlatelet‐derived growth factor BB, a potent mitogen of pulmonary artery smooth muscle cells (PASMCs), has been implicated in pulmonary arterial remodeling, which is a key pathogenic feature of pulmonary arterial hypertension. Previous microRNA profiling in platelet‐derived growth factor BB–treated PASMCs found a significantly downregulated microRNA, miR‐1281, but it has not been associated with any cellular function, and we investigated the possibility.Methods and ResultsReal‐time quantitative reverse transcription–polymerase chain reaction assay proved that downregulation of miR‐1281 was a conserved phenomenon in human and rat PASMCs. Overexpression and inhibition of miR‐1281 in PASMCs promoted and suppressed, respectively, the cell proliferation and migration. Bioinformatic prediction and 3′‐untranslated region reporter assay identified histone deacetylase 4 to be a direct target of miR‐1281. Supporting this, proliferation and migration assay demonstrated the cellular function of histone deacetylase 4 is inversely correlated with that of miR‐1281. Mechanistically, it is found that platelet‐derived growth factor BB activates the phosphatidylinositol 3‐kinase pathway, which then induces the expression of DNA methyltransferase 1, leading to enhanced methylation of a flanking CpG island and repressed miR‐1281 expression. Finally, a reduced miR‐1281 level was consistently identified in hypoxic PASMCs in vitro, in pulmonary arteries of rats with monocrotaline‐induced pulmonary arterial hypertension, and in serum of patients with coronary heart disease–pulmonary arterial hypertension. These data suggest that there may be a diagnostic and therapeutic use for miR‐1281.ConclusionsHerein, we report a novel regulatory axis, phosphatidylinositol 3‐kinase–DNA methyltransferase 1–miR‐1281–histone deacetylase 4, integrating multiple epigenetic regulators that participate in platelet‐derived growth factor BB–stimulated PASMC proliferation and migration and pulmonary vascular remodeling.

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“…Finally, contractility of PASMCs is inhibited by several miRNAs. Especially miR-223 is especially important in the regulation of actomyosin contractility by targeting upstream regulators such as ITGB3, RhoB, and MLC2 (165,166). Furthermore, calcium levels are important for contractility and are regulated by CaSR, which is targeted by two miRNAs -miR-429 and miR-424-5p (167).…”

Section: Micro Rnamentioning

confidence: 99%

Targeting epigenetic mechanisms as an emerging therapeutic strategy in pulmonary hypertension disease

et al. 2020

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Pulmonary arterial hypertension (PAH) is a multifactorial cardiopulmonary disease characterized by an elevation of pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR), which can lead to right ventricular (RV) failure, multi-organ dysfunction, and ultimately to premature death. Despite the advances in molecular biology, the mechanisms underlying pulmonary hypertension (PH) remain unclear. Nowadays, there is no curative treatment for treating PH. Therefore, it is crucial to identify novel, specific therapeutic targets and to offer more effective treatments against the progression of PH. Increasing amounts of evidence suggest that epigenetic modification may play a critical role in the pathogenesis of PAH. In the presented paper, we provide an overview of the epigenetic mechanisms specifically, DNA methylation, histone acetylation, histone methylation, and ncRNAs. As the recent identification of new pharmacological drugs targeting these epigenetic mechanisms has opened new therapeutic avenues, we also discuss the importance of epigenetic-based therapies in the context of PH.

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MicroRNA-223 Attenuates Hypoxia-induced Vascular Remodeling by Targeting RhoB/MLC2 in Pulmonary Arterial Smooth Muscle Cells

Cited by 64 publications

References 56 publications

Matrix stiffness regulates endosomal escape of uropathogenicE. coli

Matrix stiffness regulates endosomal escape of uropathogenicE. coli

Phosphatidylinositol 3‐Kinase–DNA Methyltransferase 1–miR‐1281–Histone Deacetylase 4 Regulatory Axis Mediates Platelet‐Derived Growth Factor–Induced Proliferation and Migration of Pulmonary Artery Smooth Muscle Cells

Targeting epigenetic mechanisms as an emerging therapeutic strategy in pulmonary hypertension disease

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