Propranolol-Mediated Attenuation of MMP-9 Excretion in Infants With Hemangiomas

Sheik Zayed Center for Pediatric Surgical Innovation, Children's National Medical Center, Washington, DC.
JAMA Otolaryngology - Head and Neck Surgery (Impact Factor: 1.79). 10/2013; 139(10):1026-31. DOI: 10.1001/jamaoto.2013.4773
Source: PubMed


IMPORTANCE Infantile hemangiomas (IHs) vary substantially in localization and extent of tissue involvement, but IH biological progression is remarkably unique and predictable. Propranolol is an effective treatment for symptomatic IH, but its mechanism of action remains unknown and understudied. OBJECTIVE To compare excreted proteins in infants with IH being treated with propranolol vs prednisolone. DESIGN, SETTING, AND PARTICIPANTS Exploratory urine proteomics profiling of patients with IH from July 2010 to September 2012 at a tertiary pediatric hospital. Participants were infants with IH treated at our institution who were participating in a blinded, randomized trial comparing prednisolone vs propranolol. They ranged in age from 14 days to 15 months at enrollment. Exclusion criteria included a history of diabetes mellitus, asthma, and/or cardiovascular disease including hypertension or hypotension. Urine samples were longitudinally collected from all participants. Specimens were desalted, concentrated, and gel fractionated, and the protein content was identified using liquid chromatography tandem mass spectrometry. Western blot analyses and enzyme-linked immunosorbent assays (ELISAs) were performed to validate mass spectrometry findings. INTERVENTION Treatment with propranolol or prednisolone administered starting before the age of 6 months. MAIN OUTCOMES AND MEASURES Proteins present in urine samples and change in urinary levels of proteins over time. RESULTS Samples were obtained from 3 patients treated with prednisolone, 3 patients treated with propranolol, and 5 untreated controls with IH. More than 1000 urinary proteins were identified by proteomics. Patients treated with propranolol demonstrated attenuation of excreted matrix metalloproteinase 9 (MMP-9) in urine over the proliferative phase of the condition compared with prednisolone-treated patients. These findings were validated with Western blot analysis and quantified with ELISA, which confirmed mean urinary MMP-9 levels in the first year of life to be significantly lower in propranolol-treated patients with IH compared with prednisolone-treated patients with IH (0.118 vs 0.501 ng/mL; P = .03) or with nontreated patients with IH (0.118 vs 3.69 ng/mL; P = .02). CONCLUSIONS AND RELEVANCE Propranolol treatment decreases urinary excretion of MMP-9 in patients with IH. Matrix metalloproteinase 9 may be a biomarker for IH propranolol responsiveness, and its signaling pathways may represent the molecular target of this drug.

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    ABSTRACT: Currently, propranolol is the preferred treatment for problematic proliferating infantile hemangiomas (IHs). The rapid action of propranolol has been shown to be especially dramatic in IHs involving dyspnea, hemodynamic compromise, palpebral occlusion, or ulceration. Another remarkable aspect of propranolol treatment that was revealed was that not only was the growth of the IHs stabilized, but the improvement continued until complete involution was achieved, leading to a considerable shortening of the natural course of IH. However, the mechanisms underlying the effects of propranolol have not been fully elucidated. Recent studies have offered evidence of a variety of mechanisms. These include the promotion of pericyte-mediated vasoconstriction, the inhibition of vasculogenesis and catecholamine-induced angiogenesis, the disruption of hemodynamic force-induced cell survival, and the inactivation of the rennin-angiotensin system. This review summarizes these mechanisms and the new concepts that are emerging in this area of research. Moreover, several molecular mechanisms by which propranolol may modify neovascularization in IH have also been proposed. The antihemangioma effect of propranolol may not be attributable to a single mechanism, but rather, to a combination of events that have not yet been elucidated or understood. Further studies are needed to evaluate and verify these mechanisms to gain a greater understanding of the effects of propranolol intake on hemangioma involution.This article is protected by copyright. All rights reserved.
    British Journal of Dermatology 09/2014; 172(1). DOI:10.1111/bjd.13388 · 4.28 Impact Factor
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    ABSTRACT: The serendipitous demonstration that the nonselective β-adrenergic receptor (β-AR) antagonist propranolol promotes the regression of infantile hemangiomas (IHs) aroused interest around the involvement of the β-adrenergic system in angiogenic processes. The efficacy of propranolol was related to the β2-AR blockade and the consequent inhibition of the production of vascular endothelial growth factor (VEGF), suggesting the hypothesis that propranolol could also be effective in treating retinopathy of prematurity (ROP), a retinal pathology characterized by VEGF-induced neoangiogenesis. Consequent to the encouraging animal studies, a pilot clinical trial showed that oral propranolol protects newborns from ROP progression, even though this treatment is not sufficiently safe. Further, animal studies clarified the role of β3-ARs in the development of ROP and, together with several preclinical studies demonstrating the key role of the β-adrenergic system in tumor progression, vascularization, and metastasis, prompted us to also investigate the participation of β3-ARs in tumor growth. The aim of this review is to gather the recent findings on the role of the β-adrenergic system in IHs, ROP, and cancer, highlighting the fact that these different pathologies, triggered by different pathogenic noxae, share common pathogenic mechanisms characterized by the presence of hypoxia-induced angiogenesis, which may be contrasted by targeting the β-adrenergic system. The mechanisms characterizing the pathogenesis of IHs, ROP, and cancer may also be active during the fetal–neonatal development, and a great contribution to the knowledge on the role of β-ARs in diseases characterized by chronic hypoxia may come from research focusing on the fetal and neonatal period.
    Medicinal Research Reviews 12/2014; 35(3). DOI:10.1002/med.21336 · 8.43 Impact Factor
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    ABSTRACT: Background Infantile hemangioma (IH) is a benign vascular neoplasm resulting from the abnormal proliferation of endothelial cells and pericytes in infants. Propranolol, a non-selective β-adrenergic blocker, has recently emerged as an effective therapy for IH, causing regression. However, its potential therapeutic mechanism remains largely unknown.ProcedureAn XPTS-1 cell line was established by isolating hemangioma-derived endothelial cells (HemECs) from a specimen of human proliferating IH. Flow cytometer assay was performed to assess the effect of propranolol on cell cycle distribution. Western blot was employed to determine changes of protein expression. Matrigel invasion and tube formation assays were used to measure invasion ability and tube formation ability, respectively. Commercial kits were employed to quantify NO and VEGF levels.ResultsPropranolol blocked norepinephrine-induced HemECs cell cycle progression as well as the expression of cyclin A2 and cyclin D2; whereas p21 and p27 proteins were altered conversely. Propranolol inhibited norepinephrine-induced cell invasion by reducing the expression of MMP-9, VEGF, and p-cofilin. NO and VEGF release induced by norepinephrine was decreased by propranolol pretreatment, coincident with alterations in the phosphorylation of Akt, eNOS, and VEGFR-2. Tube formation ability and subsequent levels of NO and VEGF elevated by norepinephrine were distinctively counteracted in HemECs.Conclusions The current study demonstrated the antiangiogenic properties of propranolol in vitro and that the drug was able to induce the regression of hemangioma cells via the inhibition of cell cycle progression, invasion, and tube formation, concomitantly with decreased NO and VEGF levels through the down-regulation of the PI3K/Akt/eNOS/VEGF pathway. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 02/2015; 62(8). DOI:10.1002/pbc.25453 · 2.39 Impact Factor

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