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

Abstract

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.

Suppression of transient receptor potential melastatin 4 expression promotes conversion of endothelial cells into fibroblasts via transforming growth factor/activin receptor-like kinase 5 pathway

“…These findings are in agreement with the data presented here, as endothelial cells transfected with siRNA-TRPM4 adopt a fibrotic-like phenotype in addition to acquiring several fibrotic markers and losing endothelial proteins. TRPM4 downregulation induces a change in the protein expression pattern of endothelial cells that promotes fibrotic-like protein expression similar to that previously reported in nontransfected wild-type endothelial cells exposed to TGF-b1 and TGF-b2 [8,9,49,50]. We observed that endothelial cells express and secrete both of these TGF-b isoforms when TRPM4 expression was suppressed.…”

Endotoxin-induced skeletal muscle wasting is prevented by angiotensin-(1–7) through a p38 MAPK-dependent mechanism

“…Future experiments must focus on evaluating the effect of Ang-(1-7) on oxidative stress in muscle wasting induced by LPS and evaluating the possible antioxidant role of this peptide in this model. LPS has been reported to induce the expression of TGF-β1 (transforming growth factor β1) in endothelial cells [74][75][76]. Furthermore, TGF-β1 is capable of inducing skeletal muscle atrophy [77] through UPP activation and the up-regulation of atrogin-1 and MuRF-1 [78].…”

Endothelial-to-mesenchymal transition in lipopolysaccharide-induced acute lung injury drives a progenitor cell-like phenotype

“…We defined the PVECs that underwent EndMT (EndMTPVECs) as those showing double labeling with antibodies against CD31 and ␣-SMA, or with antibodies against CD31 and S100A4 (15)(16)(17). Changes in the number of EndMTPVECs after LPS challenge are shown in Fig.…”

“…Growing evidence suggests that EndMT is enhanced or triggered by various factors including transforming growth factor-␤ (TGF-␤), hepatocyte growth factor, fibroblast growth factor, and so on. TGF-␤ is likely to be the most potent among factors that induce EndMT (17,19,28).…”