Endotoxin Induces Fibrosis in Vascular Endothelial Cells through a Mechanism Dependent on Transient Receptor Protein Melastatin 7 Activity

Echeverría, César; Montorfano, Ignacio; Hermosilla, Tamara; Armisén, Ricardo; Velásquez, Luís; Cabello-Verrugio, Claudio; Varela, Diego; Simón, Felipe

doi:10.1371/journal.pone.0094146

Cited by 35 publications

(30 citation statements)

References 65 publications

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“…3A, B, E, and F) and an increase in the fibrotic marker ␣-SMA (Fig. 3C, D, G, and H), similar to what has been observed in nontransfected wild-type ECs exposed to endotoxin (9,10,18). Note that ECs transfected with siTGF␤1 or siTGF␤2 and exposed to endotoxin were resistant to fibrosis development, as those cells did not show any significant change in the protein level of VE-cadherin (Fig.…”

Section: Endotoxin Induces the Expression Of Tgf-␤1 And Tgf-␤2supporting

confidence: 82%

Endotoxin-Induced Endothelial Fibrosis Is Dependent on Expression of Transforming Growth Factors β1 and β2

et al. 2014

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f During endotoxemia-induced inflammatory disease, bacterial endotoxins circulate in the bloodstream and interact with endothelial cells (ECs), inducing dysfunction of the ECs. We previously reported that endotoxins induce the conversion of ECs into activated fibroblasts. Through endotoxin-induced endothelial fibrosis, ECs change their morphology and their protein expression pattern, thereby suppressing endothelial markers and upregulating fibrotic proteins. The most commonly used fibrotic inducers are transforming growth factor ␤1 (TGF-␤1) and TGF-␤2. However, whether TGF-␤1 and TGF-␤2 participate in endotoxin-induced endothelial fibrosis remains unknown. We have shown that the endotoxin-induced endothelial fibrosis process is dependent on the TGF-␤ receptor, ALK5, and the activation of Smad3, a protein that is activated by ALK5 activation, thus suggesting that endotoxin elicits TGF-␤ production to mediate endotoxin-induced endothelial fibrosis. Therefore, we investigated the dependence of endotoxin-induced endothelial fibrosis on the expression of TGF-␤1 and TGF-␤2. Endotoxin-treated ECs induced the expression and secretion of TGF-␤1 and TGF-␤2. TGF-␤1 and TGF-␤2 downregulation inhibited the endotoxininduced changes in the endothelial marker VE-cadherin and in the fibrotic proteins ␣-SMA and fibronectin. Thus, endotoxin induces the production of TGF-␤1 and TGF-␤2 as a mechanism to promote endotoxin-induced endothelial fibrosis. To the best of our knowledge, this is the first report showing that endotoxin induces endothelial fibrosis via TGF-␤ secretion, which represents an emerging source of vascular dysfunction. These findings contribute to understanding the molecular mechanism of endotoxin-induced endothelial fibrosis, which could be useful in the treatment of inflammatory diseases.

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Section: Endotoxin Induces the Expression Of Tgf-␤1 And Tgf-␤2supporting

confidence: 82%

Endotoxin-Induced Endothelial Fibrosis Is Dependent on Expression of Transforming Growth Factors β1 and β2

et al. 2014

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“…Interestingly, recent studies documented that miR-126 overexpression downregulates the mRNA levels of the fibrotic marker α-smooth muscle actin. 31 We thus explored the impact of miR-126 modulation on RV fibrosis and confirmed that mimic-126 injections were also associated with decreased RV fibrosis, whereas antagomiR treatment was associated with increased fibrosis (Masson trichrome; Figure 7E and Figure VIJ in the online-only Data Supplement). Note that miR-126 upregulation did not affect VEGF or VEGFR2 expression (data not shown).…”

Section: Systemic Mir-126 Upregulation Improves Rv Function In Monocrmentioning

confidence: 76%

“…For example, miR-34 and miR-21 were found to be downregulated and miR-1 upregulated in the PA-banding model. 31 Downregulation of miR-1 and miR-133 was also observed in the PA-banding model 32 compared with the Sugen/hypoxia model. 33 Nonetheless, the role of these miRNAs in the pathogenesis of RV failure is unknown.…”

Section: Discussionmentioning

confidence: 93%

Downregulation of MicroRNA-126 Contributes to the Failing Right Ventricle in Pulmonary Arterial Hypertension

et al. 2015

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R ight ventricular (RV) function is a major determinant of functional capacity and survival in pulmonary arterial hypertension (PAH) and other types of pulmonary hypertension.1 Although afterload is a prominent determinant for RV systolic function in PAH, there remains significant variability between patients with PAH in the ability of the RV to adapt to pressure overload and pulmonary resistance.2,3 The mechanisms accounting for this variability in RV adaptability to increased pulmonary load and for the transition to RV failure remain elusive. Despite the tremendous attention that left ventricular (LV) failure has received, RV failure has remained understudied at both the preclinical and clinical levels. 3 As a result, RV failure has emerged as an important research priority in the cardiopulmonary research field. Clinical Perspective on p 943Magnetic resonance imaging performed in patients with PAH has shown that the hypertrophied RV is ischemic 5 andBackground-Right ventricular (RV) failure is the most important factor of both morbidity and mortality in pulmonary arterial hypertension (PAH). However, the underlying mechanisms resulting in the failed RV in PAH remain unknown. There is growing evidence that angiogenesis and microRNAs are involved in PAH-associated RV failure. We hypothesized that microRNA-126 (miR-126) downregulation decreases microvessel density and promotes the transition from a compensated to a decompensated RV in PAH. Methods and Results-We studied RV free wall tissues from humans with normal RV (n=17), those with compensated RV hypertrophy (n=8), and patients with PAH with decompensated RV failure (n=14). Compared with RV tissues from patients with compensated RV hypertrophy, patients with decompensated RV failure had decreased miR-126 expression (quantitative reverse transcription-polymerase chain reaction; P<0.01) and capillary density (CD31 + immunofluorescence; P<0.001), whereas left ventricular tissues were not affected. miR-126 downregulation was associated with increased Sprouty-related EVH1 domain-containing protein 1 (SPRED-1), leading to decreased activation of RAF (phosphorylated RAF/RAF) and mitogen-activated protein kinase (MAPK); (phosphorylated MAPK/MAPK), thus inhibiting the vascular endothelial growth factor pathway. In vitro, Matrigel assay showed that miR-126 upregulation increased angiogenesis of primary cultured endothelial cells from patients with decompensated RV failure. Furthermore, in vivo miR-126 upregulation (mimic intravenous injection) improved cardiac vascular density and function of monocrotaline-induced PAH animals. Conclusions-RV failure in PAH is associated with a specific molecular signature within the RV, contributing to a decrease in RV vascular density and promoting the progression to RV failure. More importantly, miR-126 upregulation in the RV improves microvessel density and RV function in experimental PAH. Key Words: hypertension, pulmonary ◼ microRNAs ◼ microvessels ◼ pulmonary heart disease ◼ right ventricular failure © 2015 American Heart Assoc...

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“…However, by means of EndMT, a fibrotic-like spindle-shaped phenotype with non-connected cells is observed along with a-SMA and FSP-1 overexpression, which alters the cytoskeletal organization. [34][35][36][37][38][39][40][41][42][43] Furthermore, acquisition of ECM proteins such as fibronectin and collagen type III is a prominent functional feature of myofibroblasts that changes endothelial functionality. Healthy ECs secrete collagen type IV and low amounts of fibronectin, whereas collagen type I and type III are virtually absent, appearing only after fibrosis has been established and affecting normal endothelial function.…”

mentioning

confidence: 99%

“…The increase in ECM proteins during EndMT alters EC function because it affects the interaction between ligands and membrane receptors, protein turnover, and protein internalization. 34,36,37,[41][42][43][44][45][46][47] In addition, increased cell migration is a major distinctive feature of myofibroblasts. Because EndMT is a cellular mechanism for the conversion of polarized ECs into motile mesenchymal cells, this process is also characterized by the acquisition of migratory features.…”

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confidence: 99%

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

Montorfano

Becerra

Cerro

et al. 2014

Laboratory Investigation

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During the pathogenesis of systemic inflammation, reactive oxygen species (ROS) circulate in the bloodstream and interact with endothelial cells (ECs), increasing intracellular oxidative stress. Although endothelial dysfunction is crucial in the pathogenesis of systemic inflammation, little is known about the effects of oxidative stress on endothelial dysfunction. Oxidative stress induces several functions, including cellular transformation. A singular process of cell conversion is tendothelial-to-mesenchymal transition, in which ECs become myofibroblasts, thus losing their endothelial properties and gaining fibrotic behavior. However, the participation of oxidative stress as an inductor of conversion of ECs into myofibroblasts is not known. Thus, we studied the role played by oxidative stress in this conversion and investigated the underlying mechanism. Our results show that oxidative stress induces conversion of ECs into myofibroblasts through decreasing the levels of endothelial markers and increasing those of fibrotic and ECM proteins. The underlying mechanism depends on the ALK5/Smad3/NF-kB pathway. Oxidative stress induces the expression and secretion of TGF-b1 and TGF-b2 and p38 MAPK phosphorylation. Downregulation of TGF-b1 and TGF-b2 by siRNA technology abolished the H 2 O 2 -induced conversion. To our knowledge, this is the first report showing that oxidative stress is able to induce conversion of ECs into myofibroblasts via TGF-b secretion, emerging as a source for oxidative stress-based vascular dysfunction. Thus, oxidative stress emerges as a decisive factor in inducing conversion of ECs into myofibroblasts through a TGF-b-dependent mechanism, changing the ECs protein expression profile, and converting normal ECs into pathological ones. This information will be useful in designing new and improved therapeutic strategies against oxidative stress-mediated systemic inflammatory diseases.

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Endotoxin Induces Fibrosis in Vascular Endothelial Cells through a Mechanism Dependent on Transient Receptor Protein Melastatin 7 Activity

Cited by 35 publications

References 65 publications

Endotoxin-Induced Endothelial Fibrosis Is Dependent on Expression of Transforming Growth Factors β1 and β2

Endotoxin-Induced Endothelial Fibrosis Is Dependent on Expression of Transforming Growth Factors β1 and β2

Downregulation of MicroRNA-126 Contributes to the Failing Right Ventricle in Pulmonary Arterial Hypertension

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

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