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Original Investigation |

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

Silpa Thaivalappil, MPH1; Nancy Bauman, MD2,3; Amarel Saieg, MS1; Elizabeth Movius, MS1; Kristy J. Brown, PhD4; Diego Preciado, MD, PhD1,2,3
[+] Author Affiliations
1Sheik Zayed Center for Pediatric Surgical Innovation, Children’s National Medical Center, Washington, DC
2Division of Pediatric Otolaryngology–Head and Neck Surgery, Children’s National Medical Center, Washington, DC
3George Washington University School of Medicine, Washington, DC
4Center for Genetic Medicine, Children’s National Medical Center, Washington, DC
JAMA Otolaryngol Head Neck Surg. 2013;139(10):1026-1031. doi:10.1001/jamaoto.2013.4773.
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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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Figure 1.
Differential Regulation of Excreted Urinary Proteins in Patients With Infantile Hemangiomas (IHs)

Each dot on the x-axis represents an identified protein in the urine of children with IH. The y-axis represents the difference in the fold change of the urinary proteins’ liquid chromatography tandem mass spectrometry spectral counts over time in the propranolol-treated patients minus that in the prednisolone-treated patients. Most of the spectrometrically identified excreted proteins did not differ significantly between the 2 treatment arms. Highly negatively different proteins represent substantial decreases in the excretion of that protein in the propranolol-treated patients relative to the prednisolone-treated patients.

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Figure 2.
Western Blots for Matrix Metalloproteinase 9 (MMP-9)

Western blot results revealed strong MMP-9 signal intensity at approximately 65 kDa in all samples (molecular standards not shown). Panels show Western blot for MMP-9 in propranolol-treated patients (A) and prednisolone-treated patients (B) over time. C, Densitometry shows a relative increase in MMP-9 signal intensity in the 6-month to 8-month age group for prednisolone-treated patients; y-axis indicates the mean dpi signal for the MMP-9 band.

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Figure 3.
Enzyme-Linked Immunosorbent Assay Results for Matrix Metalloproteinase 9 (MMP-9) in Urine

Quantification of urinary MMP-9 levels indicated a significant decrease in MMP-9 excretion during the first year of life in patients with infantile hemangiomas treated with propranolol compared with those treated with prednisolone or not treated at all. Error bars indicate standard error of the mean.

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