AI Article Synopsis
- The small molecule indirubin-3'-monoxime (I3MO) inhibits vascular smooth muscle cell (VSMC) growth by blocking the activation of STAT3.
- The study identifies 12/15-lipoxygenase (12/15-LO) as a key source of reactive oxygen species (ROS) that mediate PDGF-induced STAT3 activation, rather than NADPH oxidases or mitochondria.
- I3MO not only reduces PDGF-induced ROS production but also impacts 12/15-LO activity, highlighting its potential role in regulating STAT3 signaling in vascular smooth muscle cells.
Article Abstract
We showed previously that the small molecule indirubin-3'-monoxime (I3MO) prevents vascular smooth muscle cell (VSMC) proliferation by selectively inhibiting signal transducer and activator of transcription 3 (STAT3). Looking for the underlying upstream molecular mechanism, we here reveal the important role of reactive oxygen species (ROS) for PDGF-induced STAT3 activation in VSMC. We show that neither NADPH-dependent oxidases (Noxes) nor mitochondria, but rather 12/15-lipoxygenase (12/15-LO) are pivotal ROS sources involved in the redox-regulated signal transduction from PDGFR to STAT3. Accordingly, pharmacological and genetic interference with 12/15-LO activity selectively inhibited PDGF-induced Src activation and STAT3 phosphorylation. I3MO is able to blunt PDGF-induced ROS and 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) production, indicating an inhibitory action of I3MO on 12/15-LO and consequently on STAT3. We identify 12/15-LO as a hitherto unrecognized signaling hub in PDGF-triggered STAT3 activation and show for the first time a negative impact of I3MO on 12/15-LO.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3853304 | PMC |
| http://dx.doi.org/10.1074/jbc.M113.489013 | DOI Listing |
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