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Open Access Research article

Membrane Sealant Poloxamer P188 Protects Against Isoproterenol Induced Cardiomyopathy in Dystrophin Deficient Mice

Christopher F Spurney123, Alfredo D Guerron3, Qing Yu3, Arpana Sali3, Jack H van der Meulen3, Eric P Hoffman23 and Kanneboyina Nagaraju23*

Author Affiliations

1 Children's National Heart Institute, Division of Cardiology, Children's National Medical Center, Washington, DC USA

2 Department of Integrative Systems Biology, George Washington University School of Medicine and Public Health, Washington, DC USA

3 Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC USA

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BMC Cardiovascular Disorders 2011, 11:20  doi:10.1186/1471-2261-11-20

Published: 16 May 2011

Abstract

Background

Cardiomyopathy in Duchenne muscular dystrophy (DMD) is an increasing cause of death in patients. The absence of dystrophin leads to loss of membrane integrity, cell death and fibrosis in cardiac muscle. Treatment of cardiomyocyte membrane instability could help prevent cardiomyopathy.

Methods

Three month old female mdx mice were exposed to the β1 receptor agonist isoproterenol subcutaneously and treated with the non-ionic tri-block copolymer Poloxamer P188 (P188) (460 mg/kg/dose i.p. daily). Cardiac function was assessed using high frequency echocardiography. Tissue was evaluated with Evans Blue Dye (EBD) and picrosirius red staining.

Results

BL10 control mice tolerated 30 mg/kg/day of isoproterenol for 4 weeks while death occurred in mdx mice at 30, 15, 10, 5 and 1 mg/kg/day within 24 hours. Mdx mice tolerated a low dose of 0.5 mg/kg/day. Isoproterenol exposed mdx mice showed significantly increased heart rates (p < 0.02) and cardiac fibrosis (p < 0.01) over 4 weeks compared to unexposed controls. P188 treatment of mdx mice significantly increased heart rate (median 593 vs. 667 bpm; p < 0.001) after 2 weeks and prevented a decrease in cardiac function in isoproterenol exposed mice (Shortening Fraction = 46 ± 6% vs. 35 ± 6%; p = 0.007) after 4 weeks. P188 treated mdx mice did not show significant differences in cardiac fibrosis, but demonstrated significantly increased EBD positive fibers.

Conclusions

This model suggests that chronic intermittent intraperitoneal P188 treatment can prevent isoproterenol induced cardiomyopathy in dystrophin deficient mdx mice.

Keywords:
Duchenne muscular dystrophy; mdx; poloxamer; cardiomyopathy; isoproterenol