期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 102, 期 -, 页码 45-52出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2016.11.011
关键词
Duchenne muscular dystrophy; DMD; Duchenne cardiomyopathy; Dystrophin; Gene therapy; Heart; Low-level expression; Dilated cardiomyopathy; Adeno-associated virus; MV; ECG; Hemodynamics
资金
- National Institutes of Health [HL-91883, NS-90634, AR-69085]
- Department of Defense [MD130014, MD150133]
- Jesse's Journey-The Foundation for Gene and Cell Therapy
- University of Missouri
Dystrophin deficiency results in Duchenne cardiomyopathy, a primary cause of death in Duchenne muscular dystrophy (DMD). Gene therapy has shown great promise in ameliorating the cardiac phenotype in mouse models of DMD. However, it is not completely clear how much dystrophin is required to treat dystrophic heart disease. We and others have shown that mosaic dystrophin expression at the wild-type level, depending on the percentage of dystrophin positive cardiomyocytes, can either delay the onset of or fully prevent cardiomyopathy in dystrophinnull mdx mice. Many gene therapy strategies will unlikely restore dystrophin to the wild-type level in a cardiomyocyte. To determine whether low-level dystrophin expression can reduce the cardiac manifestations in DMD, we examined heart histology, ECG and hemodynamics in 21-m-old normal BL6 and two strains of BL6-background dystrophin-deficient mice. Mdx3cv mice show uniform low-level expression of a near full-length dystrophin protein in every myofiber while mdx4cv mice have no dystrophin expression. Immunostaining and western blot confirmed marginal level dystrophin expression in the heart of mdx3cv mice. Although low-level expression did not reduce myocardial histopathology, it significantly ameliorated QRS prolongation and normalized diastolic hemodynamic deficiencies. Our study demonstrates for the first time that low-level dystrophin can partially preserve heart function. (C) 2016 Elsevier Ltd. All rights reserved.
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