Experimental Lung Injury Reduces Krüppel-like Factor 2 to Increase Endothelial Permeability via Regulation of RAPGEF3–Rac1 Signaling

Huang, Ru-Ting; Wu, David; Meliton, Angelo Y.; Oh, Myounghak; Krause, Matthew; Lloyd, Joyce A.; Niğdelioğlu, Recep; Hamanaka, Robert B.; Jain, Mukesh K.; Birukova, Anna A.; Kress, John P.; Birukov, Konstantin G.; Mutlu, Gökhan M.; Fang, Yun

doi:10.1164/rccm.201604-0668oc

Cited by 56 publications

(54 citation statements)

References 54 publications

(63 reference statements)

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“…Thus, an optimal level of miR‐483 in pulmonary endothelium may mitigate PAH‐related EC dysfunction. Indeed, miR‐483 overexpression in cultured PAECs induced the expression of genes critical for EC homeostasis that include Krüppel‐like factor 2 (KLF2), KLF4, eNOS, ACE2, and APLNR (; Shen et al , ; Alastalo et al , ; Huang et al , ; Zhang et al , ). Interestingly, KLF4 overexpression, statins treatment, and pulsatile shear stress, known to enhance endothelial function, also increase the expression of miR‐483 in ECs (He et al , ; Fernandez Esmerats et al , ).…”

Section: Discussionmentioning

confidence: 99%

Micro RNA ‐483 amelioration of experimental pulmonary hypertension

Zhang

Yan

et al. 2020

EMBO Mol Med

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Endothelial dysfunction is critically involved in the pathogenesis of pulmonary arterial hypertension (PAH) and that exogenously administered microRNA may be of therapeutic benefit. Lower levels of miR-483 were found in serum from patients with idiopathic pulmonary arterial hypertension (IPAH), particularly those with more severe disease. RNA-seq and bioinformatics analyses showed that miR-483 targets several PAH-related genes, including transforming growth factor-b (TGF-b), TGF-b receptor 2 (TGFBR2), b-catenin, connective tissue growth factor (CTGF), interleukin-1b (IL-1b), and endothelin-1 (ET-1). Overexpression of miR-483 in ECs inhibited inflammatory and fibrogenic responses, revealed by the decreased expression of TGF-b, TGFBR2, b-catenin, CTGF, IL-1b, and ET-1. In contrast, inhibition of miR-483 increased these genes in ECs. Rats with EC-specific miR-483 overexpression exhibited ameliorated pulmonary hypertension (PH) and reduced right ventricular hypertrophy on challenge with monocrotaline (MCT) or Sugen + hypoxia. A reversal effect was observed in rats that received MCT with inhaled lentivirus overexpressing miR-483. These results indicate that PAH is associated with a reduced level of miR-483 and that miR-483 might reduce experimental PH by inhibition of multiple adverse responses.

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Section: Discussionmentioning

confidence: 99%

Micro RNA ‐483 amelioration of experimental pulmonary hypertension

Zhang

Yan

et al. 2020

EMBO Mol Med

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“…Highly interconnected networks are predicted to represent a significant biological function [23] . IPA was used to connect 132 genome-wide association study (GWAS)- implicated cancer genes along with microRNA and various cancer pathways [ 24 , 25 ]. Significantly changed miRNAs associated with Akt1 inhibition from the two experimental sets were uploaded in IPA and core analyzed.…”

Section: Methodsmentioning

confidence: 99%

Modulation in the microRNA repertoire is responsible for the stage-specific effects of Akt suppression on murine neuroendocrine prostate cancer

Alwhaibi

Gao

Artham

et al. 2018

Heliyon

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Recent studies indicate a stage-specific, differential role for the oncogene Akt on various cancers. In prostate cancer (PCa), suppression of Akt activity in the advanced stages promoted transforming growth factor-β (TGFβ) pathway-mediated epithelial-to-mesenchymal transition (EMT) and metastasis to the lungs. In the current study, we performed Affymetrix analysis to compare the expression profile of microRNAs in the mouse prostate tissues collected at the prostatic inter-epithelial neoplasia (PIN) stage from Transgenic adenocarcinoma of the mouse (TRAMP)/Akt1+/+ versus TRAMP/Akt1–/– mice, and at the advanced stage from TRAMP/Akt1+/+ mice treated with triciribine (Akt inhibitor) versus DMSO-treated control. Our analysis demonstrates that in the early stage, Akt1 in the TRAMP prostate tumors express a set of miRNAs responsible for regulating cancer cell survival, proliferation, and tumor growth, whereas, in the advanced stages, a different set of miRNAs that promote EMT and cancer metastasis is expressed. Our study has identified novel Akt-regulated signature microRNAs in the early and advanced PCa and demonstrates their differential effects on PCa growth and metastasis.

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“…Studies have shown that thyroid hormone and glucocorticoid receptors are important mediators in lung development and KLF2 is a necessary regulator for thyroid hormone and silencing mediator of retinoid and thyroid hormone receptors (SMRT)-mediated maturation of type I pneumocytes in the lung [ 17 ]. It has been also shown that lung KLF2 expression is significantly reduced in vivo rodent models on exposure to acute lung injury by influenza virus, lipopolysaccharides (LPS), or high-tidal-volume mechanical ventilation [ 18 ]. Endothelial barrier integrity is maintained by KLF2 and guanine nucleotide exchange factor 3 (RAPGEF3)-Ras-related C3 botulinum toxin substrate (RAC)1-mediated signaling.…”

Section: Kruppel Like Factormentioning

confidence: 99%

KLF2 in Regulation of NF-κB-Mediated Immune Cell Function and Inflammation

Jha

Das

2017

IJMS

124

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KLF2 (Kruppel-like factor 2) is a member of the zinc finger transcription factor family, which critically regulates embryonic lung development, function of endothelial cells and maintenance of quiescence in T-cells and monocytes. It is expressed in naïve T-cells and monocytes, however its level of expression decreases during activation and differentiation. KLF2 also plays critical regulatory role in various inflammatory diseases and their pathogenesis. Nuclear factor-kappaB (NF-κB) is an important inducer of inflammation and the inflammation is mediated through the transcription of several proinflammatory cytokines, chemokines and adhesion molecules. So, both transcriptional factors KLF2 and NF-κB are being associated with the similar cellular functions and their maintenance. It was shown that KLF2 regulates most of the NF-κB-mediated activities. In this review, we focused on emphasizing the involvement of KLF2 in health and disease states and how they interact with transcriptional master regulator NF-κB.

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Experimental Lung Injury Reduces Krüppel-like Factor 2 to Increase Endothelial Permeability via Regulation of RAPGEF3–Rac1 Signaling

Abstract: Disruption of endothelial KLF2 results in dysregulation of lung microvascular homeostasis and contributes to lung pathology in ARDS.

Cited by 56 publications

References 54 publications

Micro RNA ‐483 amelioration of experimental pulmonary hypertension

Micro RNA ‐483 amelioration of experimental pulmonary hypertension

Modulation in the microRNA repertoire is responsible for the stage-specific effects of Akt suppression on murine neuroendocrine prostate cancer

KLF2 in Regulation of NF-κB-Mediated Immune Cell Function and Inflammation

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