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.

Highlights

  • The exact regulatory mechanisms are not yet understood, many studies have found increased apoptotic signals in vascular cells of atherosclerotic plaques compared to normal vessels [1,2,3,4]

  • To determine whether TGF-β1 release could be stimulated by triglyceride-rich lipoproteins (TGRL) lipolysis products, we analyzed both cell culture supernatants and cell lysates for TGF-β1 by ELISA

  • The rate of release of TGF-β1 into cell culture supernatants was significantly increased for TGRL lipolysis products (TL) treatments relative to media (M), or lipoprotein lipase (LpL) (L) or TGRL (T) alone at 15 min (Fig 1)

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Summary

Introduction

The exact regulatory mechanisms are not yet understood, many studies have found increased apoptotic signals in vascular cells of atherosclerotic plaques compared to normal vessels [1,2,3,4]. Well-known risk factors for the development of atherosclerosis, such as high glucose

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