Lipopolysaccharide induces a fibrotic‐like phenotype in endothelial cells

Echeverría, César; Montorfano, Ignacio; Sarmiento, Daniela; Becerra, Alvaro; Nuñez-Villena, Felipe; Figueroa, Xavier F.; Cabello-Verrugio, Claudio; Elorza, Álvaro A.; Riedel, Claudia A.; Simón, Felipe

doi:10.1111/jcmm.12066

Cited by 56 publications

(78 citation statements)

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“…We previously reported that bacterial endotoxins induce the conversion of ECs into activated fibroblasts, also known as myofibroblasts (9). Endotoxin-induced endothelial fibrosis is mediated through a process known as endothelial-to-mesenchymal transition (EndMT), which has been studied using transforming growth factors ␤1 and ␤2 (TGF-␤1 and TGF-␤2) as EndMT inducers (10,11).…”

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

et al. 2014

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“…41,56,57 Furthermore, we recently demonstrated that the endotoxin lipopolysaccharide induces the acquisition of fibrotic-like phenotype in ECs. 37 This conversion rises as a potential mechanism that begins endothelial dysfunction during the inflammatory process.…”

Section: Discussionmentioning

confidence: 99%

“…ECs in the absence of H 2 O 2 showed VE-cadherin labeling that was localized predominantly to the plasma membrane (Figure 2a To demonstrate that our findings were obtained from a culture of human ECs without contamination from fibroblast-like cells, we carried out an exhaustive inspection of the EC culture. 37 To that end, we used the specific endothelial marker VE-cadherin and the specific fibrotic protein, FSP-1. We found that 499% of cells in the EC culture were positive for VE-cadherin, whereas those expressing FSP-1 were not detected.…”

Section: H 2 O 2 Induces the Conversion Of Ecs Into Myofibroblastsmentioning

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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“…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.…”

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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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LPS Promote the Odontoblastic Differentiation of Human Dental Pulp Stem Cells via MAPK Signaling Pathway

Wang

Luo

et al. 2014

Journal Cellular Physiology

103

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Human dental pulp stem cells (hDPSCs) show significant potential for exploitation in novel regeneration strategies, although lack of understanding of their responses to bacterial challenge constrains their application. The present study aimed to investigate whether lipopolysaccharide (LPS), the major pathogenic factor of Gram-negative bacteria, regulates the differentiation of hDPSCs and which intracellular signaling pathways may be involved. LPS treatment significantly promoted the differentiation of hDPSCs demonstrable by increased mineralized nodule formation and mRNA expression of several odontoblastic markers in a dose-dependent manner. While inhibition of TLR4, p38, and ERK signaling markedly antagonized LPS-mediated differentiation of hDPSCs. The inhibition of JNK and NF-κB signaling had no detectable effect on LPS activation of hDPSCs. LPS stimulation resulted in phosphorylation of NF-κB p65, IκB-α, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) in DPSCs in a time-dependent manner, which was markedly suppressed by their specific inhibitors, respectively. Data demonstrated that LPS promoted odontoblastic differentiation of hDPSCs via TLR4, ERK, and P38 MAPK signaling pathways, but not NF-κB signaling.

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Lipopolysaccharide induces a fibrotic‐like phenotype in endothelial cells

Cited by 56 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

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

LPS Promote the Odontoblastic Differentiation of Human Dental Pulp Stem Cells via MAPK Signaling Pathway

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