Dataset Information

DT-13 Ameliorates TNF-?-Induced Vascular Endothelial Hyperpermeability via Non-Muscle Myosin IIA and the Src/PI3K/Akt Signaling Pathway.

ABSTRACT: DT-13(25(R,S)-ruscogenin-1-O-[?-d-glucopyranosyl-(1?2)][?-d-xylopyranosyl-(1?3)]-?-d-fucopyranoside) has been identified as an important factor in TNF-?-induced vascular inflammation. However, the effect of DT-13 on TNF-?-induced endothelial permeability and the potential molecular mechanisms remain unclear. Hence, this study was undertaken to elucidate the protective effect of DT-13 on TNF-?-induced endothelial permeability and the underlying mechanisms in vivo and in vitro. The in vivo results showed that DT-13 could ameliorate endothelial permeability in mustard oil-induced plasma leakage in the skin and modulate ZO-1 organization. In addition, the in vitro results showed that pretreatment with DT-13 could increase the transendothelial electrical resistance value and decrease the sodium fluorescein permeability coefficient. Moreover, DT-13 altered the mRNA and protein levels of ZO-1 as determined by real-time PCR, Western blotting, and immunofluorescence analyses. DT-13 treatment decreased the phosphorylations of Src, PI3K, and Akt in TNF-?-treated human umbilical vein endothelial cells (HUVECs). Further analyses with PP2 (10?µM, inhibitor of Src) indicated that DT-13 modulated endothelial permeability in TNF-?-induced HUVECs in an Src-dependent manner. LY294002 (10?µM, PI3K inhibitor) also had the same effect on DT-13 but did not affect phosphorylation of Src. Following decreased expression of non-muscle myosin IIA (NMIIA), the effect of DT-13 on the phosphorylations of Src, PI3K, and Akt was abolished. This study provides pharmacological evidence showing that DT-13 significantly ameliorated the TNF-?-induced vascular endothelial hyperpermeability through modulation of the Src/PI3K/Akt pathway and NMIIA, which play an important role in this process.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC5557769 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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DT-13 Ameliorates TNF-α-Induced Vascular Endothelial Hyperpermeability via Non-Muscle Myosin IIA and the Src/PI3K/Akt Signaling Pathway.

Zhang Yuanyuan Y Han Yuwei Y Zhao Yazheng Y Lv Yanni Y Hu Yang Y Tan Yisha Y Bi Xueyuan X Yu Boyang B Kou Junping J

Frontiers in immunology 20170814

DT-13(25(R,S)-ruscogenin-1-O-[β-d-glucopyranosyl-(1→2)][β-d-xylopyranosyl-(1→3)]-β-d-fucopyranoside) has been identified as an important factor in TNF-α-induced vascular inflammation. However, the effect of DT-13 on TNF-α-induced endothelial permeability and the potential molecular mechanisms remain unclear. Hence, this study was undertaken to elucidate the protective effect of DT-13 on TNF-α-induced endothelial permeability and the underlying mechanisms in vivo and in vitro ...[more]

PMID: 28855900

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Project description:BACKGROUND:Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal disease. Histone deacetylase 6 (HDAC6) alters function and fate of various proteins via deacetylation of lysine residues, and is implicated in TGF-?1-induced EMT (epithelial-mesenchymal transition). However, the role of HDAC6 in pulmonary fibrosis is unknown. METHODS:HDAC6 expression in IPF and control lungs was assessed by quantitative real-time PCR (qRT-PCR) and immunoblots. Lung fibroblasts were treated with TGF-?1 ± HDAC6 inhibitors (Tubacin, Tubastatin, ACY1215, or MC1568), and fibrotic markers such as type I collagen were assessed using qRT-PCR and immunoblots. Mice were treated with bleomycin (oropharyngeal aspiration; single dose) ± Tubastatin (intraperitoneally injection; daily for 21 days), and lung collagen expression was gauged using immunoblots and trichrome staining. In a separate experiment, HDAC6 wild-type (WT) and knockout (KO) mice were administered bleomycin, and lungs were evaluated in the same manner. RESULTS:HDAC6 expression was deregulated in IPF lungs. Among the HDAC6 inhibitors tested, only Tubastatin significantly repressed TGF-?1-induced expression of type-1 collagen in lung fibroblasts, and this finding was coupled with decreased Akt phosphorylation and increased Akt-PHLPP (PH domain and Leucine rich repeat Protein Phosphatase) association. Tubastatin repressed TGF-?1-induced S6K phosphorylation, HIF-1? expression, and VEGF expression. Tubastatin also repressed TGF-?1-induced inhibition of LC3B-II (a marker of autophagosome formation). In bleomycin-treated mouse lungs, HDAC6 expression was increased, and Tubastatin repressed type-1 collagen expression. However, in HDAC6 KO mice, bleomycin-induced type-1 collagen expression was not repressed compared to WT mice. Knockdown of HDAC6, as well as HDAC10, another potential Tubastatin target, did not inhibit TGF-?1-induced collagen expression in lung fibroblasts. CONCLUSIONS:HDAC6 expression is altered during lung fibrogenesis. Tubastatin represses TGF-?1-induced collagen expression, by diminishing Akt phosphorylation and regulating downstream targets such as HIF-1?-VEGF axis and autophagy. Tubastatin-treated WT mice are protected against bleomycin-induced fibrosis, but HDAC6 KO mice are not. Our data suggest that Tubastatin ameliorates pulmonary fibrosis, by targeting the TGF?-PI3K-Akt pathway, likely via an HDAC6-independent mechanism.

Dataset Information

DT-13 Ameliorates TNF-?-Induced Vascular Endothelial Hyperpermeability via Non-Muscle Myosin IIA and the Src/PI3K/Akt Signaling Pathway.

Publications

DT-13 Ameliorates TNF-α-Induced Vascular Endothelial Hyperpermeability <i>via</i> Non-Muscle Myosin IIA and the Src/PI3K/Akt Signaling Pathway.

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