biostudies-literatureEiselein LNIA NIH HHSNHLBI NIH HHSe0145523https://www.ebi.ac.uk/biostudies/studies/S-EPMC4699200biostudies-literatureUnknown10(12)Studies have suggested a link between the transforming growth factor beta 1 (TGF-?1) signaling cascade and the stress-inducible activating transcription factor 3 (ATF3). We have demonstrated that triglyceride-rich lipoproteins (TGRL) lipolysis products activate MAP kinase stress associated JNK/c-Jun pathways resulting in up-regulation of ATF3, pro-inflammatory genes and induction of apoptosis in human aortic endothelial cells. Here we demonstrate increased release of active TGF-? at 15 min, phosphorylation of Smad2 and translocation of co-Smad4 from cytosol to nucleus after a 1.5 h treatment with lipolysis products. Activation and translocation of Smad2 and 4 was blocked by addition of SB431542 (10 ?M), a specific inhibitor of TGF-?-activin receptor ALKs 4, 5, 7. Both ALK receptor inhibition and anti TGF-?1 antibody prevented lipolysis product induced up-regulation of ATF3 mRNA and protein. ALK inhibition prevented lipolysis product-induced nuclear accumulation of ATF3. ALKs 4, 5, 7 inhibition also prevented phosphorylation of c-Jun and TGRL lipolysis product-induced p53 and caspase-3 protein expression. These findings demonstrate that TGRL lipolysis products cause release of active TGF-? and lipolysis product-induced apoptosis is dependent on TGF-? signaling. Furthermore, signaling through the stress associated JNK/c-Jun pathway is dependent on TGF-? signaling suggesting that TGF-? signaling is necessary for nuclear accumulation of the ATF3/cJun transcription complex and induction of pro-inflammatory responses.PloS oneTGRL Lipolysis Products Induce Stress Protein ATF3 via the TGF-? Receptor Pathway in Human Aortic Endothelial Cells.PMC4699200AG039094R01 AG039094R01 HL055667HL55667R01 AG045541Nyunt TWilson DWLame MWEiselein LRutledge JCNg KFAung HHfalseTGRL Lipolysis Products Induce Stress Protein ATF3 via the TGF-? Receptor Pathway in Human Aortic Endothelial Cells.Studies have suggested a link between the transforming growth factor beta 1 (TGF-?1) signaling cascade and the stress-inducible activating transcription factor 3 (ATF3). We have demonstrated that triglyceride-rich lipoproteins (TGRL) lipolysis products activate MAP kinase stress associated JNK/c-Jun pathways resulting in up-regulation of ATF3, pro-inflammatory genes and induction of apoptosis in human aortic endothelial cells. Here we demonstrate increased release of active TGF-? at 15 min, phosphorylation of Smad2 and translocation of co-Smad4 from cytosol to nucleus after a 1.5 h treatment with lipolysis products. Activation and translocation of Smad2 and 4 was blocked by addition of SB431542 (10 ?M), a specific inhibitor of TGF-?-activin receptor ALKs 4, 5, 7. Both ALK receptor inhibition and anti TGF-?1 antibody prevented lipolysis product induced up-regulation of ATF3 mRNA and protein. ALK inhibition prevented lipolysis product-induced nuclear accumulation of ATF3. ALKs 4, 5, 7 inhibition also prevented phosphorylation of c-Jun and TGRL lipolysis product-induced p53 and caspase-3 protein expression. These findings demonstrate that TGRL lipolysis products cause release of active TGF-? and lipolysis product-induced apoptosis is dependent on TGF-? signaling. Furthermore, signaling through the stress associated JNK/c-Jun pathway is dependent on TGF-? signaling suggesting that TGF-? signaling is necessary for nuclear accumulation of the ATF3/cJun transcription complex and induction of pro-inflammatory responses.2015-01-01T00:00:00Z20152021-02-20T19:21:22Z2019-03-26T22:56:47ZS-EPMC46992002670950910.1371/journal.pone.0145523