期刊
JOURNAL OF PEDIATRIC SURGERY
卷 47, 期 12, 页码 2216-2223出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1016/j.jpedsurg.2012.09.008
关键词
Infantile hemangioma; Endothelial cells; Propranolol; Proliferation; Apoptosis
Background/Purpose: Propranolol, a non-selective beta-blocker, has recently been introduced as a novel treatment modality for proliferating hemangiomas. However, the mechanism of action of this therapy is unknown. In this study, we investigated propranolol in the etiology of hemangiomas that are associated with the proliferation and apoptosis of hemangioma-derived endothelial cells (HemECs). Methods: HemECs were isolated from freshly resected hemangioma specimens. We studied propranolol-treated HemECs in vitro. We measured the effect of propranolol on HemEC viability using the Cell Counting Kit-8 (CCK-8) assay and proliferation and apoptosis using a BrdU labeling assay, annexin-V-fluorescein isothiocyanate/propidium iodide flow cytometry, and Hoechst 33342 fluorescent staining. We explored the potential mechanisms of propranolol-induced HemEC dysfunction using western blot analysis, a caspase assay kit, and real-time quantitative PCR. Results: We observed that propranolol had inhibitory effects on the viability and proliferation of HemECs. HemEC apoptosis significantly increased with 100 mu M propranolol treatment. Vascular endothelial growth factor (VEGF) expression was down-regulated by propranolol in a dose-dependent manner. We also demonstrated activation of the caspase cascade, including caspase-9 and caspase-3 of the intrinsic pathway, and an increased p53 gene expression and Bax/Bcl-xL ratio in HemECs treated with 100 mu M propranolol. Conclusions: We obtained novel data that suggests propranolol could inhibit HemEC proliferation and induce apoptosis. The effects were likely mediated through the suppression of VEGF expression, activation of caspase-9 and caspase-3, up-regulation of the pro-apoptotic genes p53 and Bax and down-regulation of the anti-apoptotic gene Bcl-xL. (C) 2012 Elsevier Inc. All rights reserved.
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