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PROPRANOLOL EFFECTS ON MESENCHYMAL STEM CELLS ARE NOT MEDIATED VIA INHIBITION OF MAPK
Presenter: Alex Kitajewski, Student
Co-Authors: Kitajewski A; Banerjee D; Shawber CJ; Kitajewski J; Wu JK
Columbia University

Purpose: The pathogenesis of infantile hemangioma (IH) is poorly understood, which has hampered development of effective, targeted medical therapy. Propranolol has been serendipitously discovered to be efficacious in the treatment of problematic IH, suggesting that beta-adrenergic signaling pathways function in IH pathobiology. We hypothesize that propranolol exerts its effect via the beta-adrenergic receptor and its downstream mediator mitogen-activated protein kinase (MAPK), and that MAPK is a potential therapeutic target for the treatment of problematic IH.

Methods: To test MAPK activation, mesenchymal stem cells (MSCs) were starved in 0.5% FBS for 24 hours. The medium was then replaced with serum-free medium (SFM) in the presence of propranolol (at 50uM or 100uM), 5uM U0126 (MAPK inhibitor), or vehicle for one hour. In one trial, MSCs were immediately lysed following the hour incubation period (Figure 1 left). In a second trial (Figure 1 right), norepinephrine (NE) was added (for a final concentration of 10uM) for ten minutes (beta-adrenergic stimulation). Equal amounts of protein were separated by SDS-PAGE electrophoresis. The presence of endogenous MAPK and activated phosphorylated MAPK-P were visualized by immunoblotting.

Results: In quiescent MSCs starved for 24 hours, phosphorylation of MAPK was not detected in the vehicle- or U0126-treated cells. Norepinephrine treatment resulted in MAPK phosphorylation. However, propranolol-treated cells showed a dose-dependent increase in MAPK phosphorylation when compared to vehicle-treated cells, contrary to prediction (Figure 1).

Conclusion: Contrary to our hypothesis, beta-blockade by propranolol did not inhibit, but activated MAPK phosphorylation. The increased MAPK activation may be a result of feedback stimulation or activation of an alternative receptor-signaling pathway. These results also suggest that the beta-adrenergic receptors signal through other downstream pathways in IH pathology. Further studies are ongoing to investigate other possible pathways.


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