title: TGRL Lipolysis Products Induce Stress Protein ATF3 via the TGF-β Receptor Pathway in Human Aortic Endothelial Cells.
abstract: Studies have suggested a link between the transforming growth factor beta 1 (TGF-β1) 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-β 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 μM), a specific inhibitor of TGF-β-activin receptor ALKs 4, 5, 7. Both ALK receptor inhibition and anti TGF-β1 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-β and lipolysis product-induced apoptosis is dependent on TGF-β signaling. Furthermore, signaling through the stress associated JNK/c-Jun pathway is dependent on TGF-β signaling suggesting that TGF-β signaling is necessary for nuclear accumulation of the ATF3/cJun transcription complex and induction of pro-inflammatory responses.
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Medicine, School of Medicine, University of California Davis, Davis, California, 95616, United States of America.
authors.forename: Larissa
authors.initials: L
authors.lastname: Eiselein
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Medicine, School of Medicine, University of California Davis, Davis, California, 95616, United States of America.
authors.forename: Tun
authors.initials: T
authors.lastname: Nyunt
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, California, 95616, United States of America.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lamé
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Medicine, School of Medicine, University of California Davis, Davis, California, 95616, United States of America.
authors.forename: Kit F
authors.initials: KF
authors.lastname: Ng
authors.affiliation: Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California Davis, Davis, California, 95616, United States of America.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Wilson
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Medicine, School of Medicine, University of California Davis, Davis, California, 95616, United States of America.
authors.forename: John C
authors.initials: JC
authors.lastname: Rutledge
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Medicine, School of Medicine, University of California Davis, Davis, California, 95616, United States of America.
authors.forename: Hnin H
authors.initials: HH
authors.lastname: Aung
mesh_terms: D051700:Activating Transcription Factor 3 / Q000096:biosynthesis*; D021581:Active Transport, Cell Nucleus; D000818:Animals; D001011:Aorta / Q000378:metabolism; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D008066:Lipolysis; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism; D013312:Stress, Physiological; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014280:Triglycerides / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D008074:Lipoproteins; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; C497796:SMAD4 protein, human; D051899:Smad2 Protein; D051901:Smad4 Protein; C495901:TP53 protein, human; D053773:Transforming Growth Factor beta1; D014280:Triglycerides; D016159:Tumor Suppressor Protein p53; C030087:lipoprotein triglyceride; C505407:CASP3 protein, human; D053148:Caspase 3