Response to Abcouwer and Roybal
Drs Abcouwer and Roybal claim that we did not acknowledge prior work linking ATF-4 to VEGF-A expression. They pointed to papers from their own group published in 20043 and 2005,4 as well as other studies by Chakraborty et al (published January 2008)5 and Oskolkova et al (May 2008).6 However, our article did, in fact, cite both Roybal articles (Refs 25 and 40; see pages 386 to 387 of Malabanan et al) and the Chakraborty article (Ref 39; see page 387 of Malabanan et al). Indeed, our article clearly states (see page 381, column 1, paragraph 2) that “previous studies have demonstrated the existence of a single functional ATF-4 binding site in the VEGF-A gene.” And after this statement, we cite Roybal et al.4 Our article even cites a third report from Dr Abcouwer and colleagues (Luo et al [Ref 26]; page 386 of Malabanan et al). Thus, we cited no fewer than 3 articles by Abcouwer and colleagues on ATF-4. We were not aware of the report by Oskolkova et al until after the publication of our article; Oskolkova et al was published online ahead of print only a few weeks before our report was published.
The above notwithstanding, in our report,1 we demonstrate the existence of an fibroblast growth factor-2/ATF-4/VEGF-A axis in vascular smooth muscle cells in the context of wound repair after balloon angioplasty, which clearly differs in disease context and stimuli from any of these prior studies. Even then, we demonstrate that the role of ATF-4 in the reparative response to injury is not confined to VEGF-A alone. The findings of the report “open up opportunities of exploring the role of ATF-4 in the regulation of pathophysiologically relevant genes besides VEGF-A” (Malabanan et al;1 page 384, column 2, paragraph 2), some of which, as reiterated by Dr Chin,2 we have already begun to establish (Figure 4B, page 382, Malabanan et al1).
Sources of Funding
Supported by funds from the National Health and Medical Research Council of Australia.
Malabanan K, Kanellakis P, Bobik A, Khachigian LM. ATF-4 induced by FGF-2 regulates VEGF-A transcription in vascular SMCs and mediates intimal thickening in rat arteries following balloon injury. Circ Res. 2008; 103: 378–387.
Chin MT. ATF-4 and vascular injury: integration of growth factor signaling and the cellular stress response. Circ Res. 2008; 103: 331–333.
Roybal CN, Yang S, Sun CW, Hurtado D, Vander Jagt DL, Townes TM, Abcouwer SF. Homocysteine increases the expression of vascular endothelial growth factor by a mechanism involving endoplasmic reticulum stress and transcription factor ATF4. J Biol Chem. 2004; 279: 14844–14852.
Roybal CN, Hunsaker LA, Barbash O, Vander Jagt DL, Abcouwer SF. The oxidative stressor arsenite activates vascular endothelial growth factor mRNA transcription by an ATF4-dependent mechanism. J Biol Chem. 2005; 280: 20331–20339.
Chakraborty G, Jain S, Kundu GC. Osteopontin promotes vascular endothelial growth factor-dependent breast tumor growth and angiogenesis via autocrine and paracrine mechanisms. Cancer Res. 2008; 68: 152–161.
Oskolkova OV, Afonyushkin T, Leitner A, von Schlieffen E, Gargalovic PS, Lusis AJ, Binder BR, Bochkov VN. ATF4-dependent transcription is a key mechanism in VEGF up-regulation by oxidized phospholipids: critical role of oxidized sn-2 residues in activation of unfolded protein response. Blood. 2008; 112: 330–339.