自噬
液泡
普萘洛尔
巴非霉素
体外
药理学
细胞生物学
化学
生物
内分泌学
细胞凋亡
生物化学
细胞质
作者
Bruno Lorusso,Giuseppe Cerasoli,Angela Falco,Caterina Frati,Gallia Graiani,Denise Madeddu,Antonella Nogara,Emilia Corradini,Giovanni Roti,Elisa Cerretani,Andrea Gherli,Mariafrancesca Caputi,Letizia Gnetti,Francesco Paolo Pilato,Federico Quaini,Costanza Lagrasta
标识
DOI:10.1016/j.vph.2022.107110
摘要
The mechanisms underlying the success of propranolol in the treatment of infantile hemangioma (IH) remain elusive and do not fully explain the rapid regression of hemangiomatous lesions following drug administration. As autophagy is critically implicated in vascular homeostasis, we determined whether β-blockers trigger the autophagic flux on infantile hemangioma-derived endothelial cells (Hem-ECs) in vitro.Fresh tissue specimens, surgically removed for therapeutic purpose to seven children affected by proliferative IH, were subjected to enzymatic digestion. Cells were sorted with anti-human CD31 immunolabeled magnetic microbeads. Following phenotypic characterization, expanded Hem-ECs, at P2 to P6, were exposed to different concentrations (50 μM to 150 μM) of propranolol, atenolol or metoprolol alone and in combination with the autophagy inhibitor Bafilomycin A1. Rapamycin, a potent inducer of autophagy, was also used as control. Autophagy was assessed by Lysotracker Red staining, western blot analysis of LC3BII/LC3BI and p62, and morphologically by transmission electron microscopy.Hem-ECs treated with either propranolol, atenolol or metoprolol displayed positive LysoTracker Red staining. Increased LC3BII/LC3BI ratio, as well as p62 modulation, were documented in β-blockers treated Hem-ECs. Abundant autophagic vacuoles and multilamellar bodies characterized the cytoplasmic ultrastructural features of autophagy in cultured Hem-ECs exposed in vitro to β-blocking agents. Importantly, similar biochemical and morphologic evidence of autophagy were observed following rapamycin while Bafilomycin A1 significantly prevented the autophagic flux promoted by β-blockers in Hem-ECs.Our data suggest that autophagy may be ascribed among the mechanisms of action of β-blockers suggesting new mechanistic insights on the potential therapeutic application of this class of drugs in pathologic conditions involving uncontrolled angiogenesis.
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