Dicer1 Deficiency in the Idiopathic Pulmonary Fibrosis Fibroblastic Focus Promotes Fibrosis by Suppressing MicroRNA Biogenesis

Herrera, Jeremy; Beisang, Daniel; Peterson, Mark S.; Forster, Colleen L.; Gilbertsen, Adam; Benyumov, Alexey O.; Smith, Karen; Korenczuk, Christopher E.; Barocas, Victor H.; Guenther, Kacey L.; Hite, Ryan; Zhang, Lin; Henke, Craig A.; Bitterman, Peter B.

doi:10.1164/rccm.201709-1823oc

Cited by 45 publications

(42 citation statements)

References 44 publications

(56 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…miR-29 deregulation plays a role in establishing pathological feedback loops that sustain the progression of fibrosis in many tissues [11]. Repression of miR-29 by stressors releases their mRNA targets from posttranscriptional inhibition [12][13][14][15][16]. Accordingly, miR-29 has been reported to be down-regulated in patients and in rodent models of progressive fibrotic diseases including those of the heart, arteries, kidneys, lungs, liver, and skin, in which functional failure of the affected organ is the usual outcome [11,15,[17][18][19][20][21][22][23][24][25].…”

Section: Introductionmentioning

confidence: 99%

Sex-Specific Regulation of miR-29b in the Myocardium Under Pressure Overload is Associated with Differential Molecular, Structural and Functional Remodeling Patterns in Mice and Patients with Aortic Stenosis

García

Salido-Medina

Gil

et al. 2020

Cells

View full text Add to dashboard Cite

Pressure overload in patients with aortic stenosis (AS) induces an adverse remodeling of the left ventricle (LV) in a sex-specific manner. We assessed whether a sex-specific miR-29b dysregulation underlies this sex-biased remodeling pattern, as has been described in liver fibrosis. We studied mice with transverse aortic constriction (TAC) and patients with AS. miR-29b was determined in the LV (mice, patients) and plasma (patients). Expression of remodeling-related markers and histological fibrosis were determined in mouse LV. Echocardiographic morpho-functional parameters were evaluated at baseline and post-TAC in mice, and preoperatively and 1 year after aortic valve replacement (AVR) in patients with AS. In mice, miR-29b LV regulation was opposite in TAC-males (down-regulation) and TAC-females (up-regulation). The subsequent changes in miR-29b targets (collagens and GSK-3β) revealed a remodeling pattern that was more fibrotic in males but more hypertrophic in females. Both systolic and diastolic cardiac functions deteriorated more in TAC-females, thus suggesting a detrimental role of miR-29b in females, but was protective in the LV under pressure overload in males. Clinically, miR-29b in controls and patients with AS reproduced most of the sexually dimorphic features observed in mice. In women with AS, the preoperative plasma expression of miR-29b paralleled the severity of hypertrophy and was a significant negative predictor of reverse remodeling after AVR; therefore, it may have potential value as a prognostic biomarker.

show abstract

Section: Introductionmentioning

confidence: 99%

Sex-Specific Regulation of miR-29b in the Myocardium Under Pressure Overload is Associated with Differential Molecular, Structural and Functional Remodeling Patterns in Mice and Patients with Aortic Stenosis

García

Salido-Medina

Gil

et al. 2020

Cells

View full text Add to dashboard Cite

show abstract

“…Over the past decade, emerging evidence has revealed potential biomarkers for the prediction of PF. According to microarray profiles, multiple miRNAs, including miR-29 (32,33), miR-326 (34), miR-98 (35) and miR-let-7d (36), may participate in the pathogenesis of PF. Herein, the expression of miR-1290 was significantly upregulated in blood samples obtained from patients with PF and in A549 cells upon TGF-β1 stimulation, and the overexpression of miR-1290 promoted A549 cell proliferation and fibrosis marker proteins levels under TGF-β1 stimulation conditions, indicating the potential of miR-1290 as a novel biomarker for PF.…”

Section: Discussionmentioning

confidence: 99%

TGF‑β1 induces CREB1‑mediated miR‑1290 upregulation to antagonize lung fibrosis via Napsin�A

Guan

Zhang

et al. 2020

Int J Mol Med

View full text Add to dashboard Cite

The pathologic mechanisms of pulmonary fibrosis (PF), one of the most common chronic pulmonary diseases, remain unclear. Napsin A is an aspartic proteinase that has been regarded as a hallmark of pulmonary adenocarcinoma. The present study aimed to investigate the specific function and molecular mechanisms of Napsin A in PF from the perspective of microRNA (miRNA or miR) regulation. In the present study, it was found that miR-1290 downregulated the expression of Napsin A by binding to its 3'-UTR. Cell viability was examined by MTT assay. The protein levels of α-smooth muscle actin (α-SMA), Collagen I and Napsin A were examined by western blot analysis. The predicted targeting of Napsin A by miR-1290 was validated by luciferase reporter assay. The protein content of α-SMA was examined by immunofluorescence staining. miR-1290 was found to be upregulated in blood samples from patients with PF and in TGF-β1-stimulated A549 cells. miR-1290 was found to directly target Napsin A. miR-1290 overexpression also significantly promoted A549 cell proliferation and increased the protein levels of markers of fibrosis. Napsin A knockdown exerted effects on A549 cell proliferation and TGF-β1-induced fibrosis that were similar to those induced by miR-1290 overexpression; more importantly, Napsin A knockdown significantly reversed the effects of miR-1290 inhibition, indicating that miR-1290 promotes TGF-β1-induced fibrosis by targeting Napsin A. Moreover, TGF-β1-induced CAMP responsive element binding protein 1 (cREB1) overexpression promoted the transcription of miR-1290 in A549 cells. On the whole, the findings of the present study demonstrate that TGF-β1-induced cREB1 overexpression induces the significant upregulation of miR-1290 expression, thus aggravating TGF-β1-induced fibrotic changes in A549 cells via the miR-1290 downstream target, Napsin A.

show abstract

“…An emerging theme is that the ECM is a driver of disease processes including atherosclerosis (34) fibrosis (35,36) and cancer (37). The strategy developed here could be applied to a multitude of settings where tissue heterogeneity is a common theme.…”

Section: Discussionmentioning

confidence: 99%

Laser capture microdissection coupled mass spectrometry (LCM-MS) for spatially resolved analysis of formalin-fixed and stained human lung tissues

Herrera

Mallikarjun

Rosini

et al. 2019

Preprint

View full text Add to dashboard Cite

Haematoxylin and eosin (H&E)which respectively stain nuclei blue and other cellular and stromal material pinkare routinely used for clinical diagnosis based on the identification of morphological features. A richer characterization can be achieved by laser capture microdissection coupled to mass spectrometry (LCM-MS), giving an unbiased assay of the proteins that make up the tissue. However, the process of fixing, and H&E staining of tissues is poorly compatible with standard sample preparation methods for mass spectrometry, resulting in low protein yield. Here we describe a microproteomics technique optimized to analyze H&E-stained, formalin-fixed paraffin-embedded (FFPE) tissues. We advance our methodology by combining 3 techniques shown to individually enhance protein yields (heat extraction, physical disruption, and in column digestion) into one optimized pipeline for the analysis of H&E stained FFPE tissues. Micro-dissected morphologically normal human lung alveoli (0.082 mm 3 ) and human lung blood vessels (0.094 mm 3 ) from FFPE fixed section from Idiopathic Pulmonary Fibrosis (IPF) specimens were then subject to comparative proteomics using this methodology. This approach yielded 1252 differentially expressed proteins including 137 extracellular matrix (ECM) proteins. In addition, we offer proof of principal that MS can identify distinct, characteristic proteomic compositions of anatomical features within complex tissues.

show abstract

Dicer1 Deficiency in the Idiopathic Pulmonary Fibrosis Fibroblastic Focus Promotes Fibrosis by Suppressing MicroRNA Biogenesis

Abstract: Our data identify suppression of fibroblast Dicer1 expression in the myofibroblast-rich IPF fibroblastic focus core as a central step in the mechanism by which the ECM sustains fibrosis progression in IPF.

Cited by 45 publications

References 44 publications

Sex-Specific Regulation of miR-29b in the Myocardium Under Pressure Overload is Associated with Differential Molecular, Structural and Functional Remodeling Patterns in Mice and Patients with Aortic Stenosis

Sex-Specific Regulation of miR-29b in the Myocardium Under Pressure Overload is Associated with Differential Molecular, Structural and Functional Remodeling Patterns in Mice and Patients with Aortic Stenosis

TGF‑β1 induces CREB1‑mediated miR‑1290 upregulation to antagonize lung fibrosis via Napsin�A

Laser capture microdissection coupled mass spectrometry (LCM-MS) for spatially resolved analysis of formalin-fixed and stained human lung tissues

Contact Info

Product

Resources

About