Seebauer, Caroline T. and Graus, Matthew S. and Huang, Lan and McCann, Alex and Wylie-Sears, Jill and Fontaine, Frank and Karnezis, Tara and Zurakowski, David and Staffa, Steven J. and Meunier, Frederic and Mulliken, John B. and Bischoff, Joyce and Francois, Mathias (2022) Non-beta blocker enantiomers of propranolol and atenolol inhibit vasculogenesis in infantile hemangioma. JOURNAL OF CLINICAL INVESTIGATION, 132 (3): e151109. ISSN 0021-9738, 1558-8238
Full text not available from this repository. (Request a copy)Abstract
Propranolol and atenolol, current therapies for problematic infantile hemangioma (IH), are composed of R(+) and S(-) enantiomers: the R(+) enantiomer is largely devoid of beta blocker activity. We investigated the effect of R(+) enantiomers of propranolol and atenolol on the formation of IH-like blood vessels from hemangioma stem cells (HemSCs) in a murine xenograft model. Both R(+) enantiomers inhibited HemSC vessel formation in vivo. In vitro, similar to R(+) propranolol, both atenolol and its R(+) enantiomer inhibited HemSC to endothelial cell differentiation. As our previous work implicated the transcription factor sex-determining region Y (SRY) box transcription factor 18 (SOX18) in propranolol-mediated inhibition of HemSC to endothelial differentiation, we tested in parallel a known SOX18 small-molecule inhibitor (Sm4) and show that this compound inhibited HemSC vessel formation in vivo with efficacy similar to that seen with the R(+) enantiomers. We next examined how R(+) propranolol alters SOX18 transcriptional activity. Using a suite of biochemical, biophysical, and quantitative molecular imaging assays, we show that R(+) propranolol directly interfered with SOX18 target gene trans activation, disrupted SOX18-chromatin binding dynamics, and reduced SOX18 dimer formation. We propose that the R(+) enantiomers of widely used beta blockers could be repurposed to increase the efficiency of current IH treatment and lower adverse associated side effects.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PROTEIN EXPRESSION; REDUNDANT ROLES; STEM-CELLS; VEGF-A; SOX18; MOLECULE; IDENTIFICATION; PREDNISOLONE; MANAGEMENT; APOPTOSIS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Hals-Nasen-Ohren-Heilkunde |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 01 Feb 2024 13:18 |
| Last Modified: | 01 Feb 2024 13:18 |
| URI: | https://pred.uni-regensburg.de/id/eprint/58415 |
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