iNOS expression in dystrophinopathies can be reduced by somatic gene transfer of dystrophin or utrophin

被引:21
作者
Louboutin, JP
Rouger, K
Tinsley, JM
Halldorson, J
Wilson, JM
机构
[1] Univ Penn, Inst Human Gene Therapy, Wistar Inst 204, Philadelphia, PA 19104 USA
[2] Univ Penn, Dept Mol & Cellular Engn, Wistar Inst 204, Philadelphia, PA 19104 USA
[3] Hotel Dieu, INSERM, UMR 533, F-44000 Nantes, France
[4] Univ Oxford, Dept Human Anat & Genet, Oxford OX1 3QU, England
关键词
D O I
10.1007/BF03402218
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Background: Nitric oxide (NO) is an inorganic gas produced by a family of NO synthase (NOS) proteins. The presence and the distribution of inducible-NOS (NC)S II or iNOS), and NADPH-diaphorase (NADPH-d), a marker for NOS catalytic activity, were determined in muscle sections from control, DMD, and BMD patients. Materials and Methods: NADPH-d reactivity, iNOS- and nNOS (NOS I)-immunolocalization were studied in muscles from mdx mice before and after somatic gene transfer of dystrophin or utrophin. Results: In control patients, few fibers (<2%) demonstrated focal accumulation of iNOS in sarcolemma. In DMD patients, a strong iNOS immunoreactivity was observed in some necrotic muscle fibers as well as in some mononuclear cells, and regenerating muscle fibers had diffusely positive iNOS immunoreactivity. In DMD patients, NADPH-d reactivity was increased and mainly localized in regenerating muscle fibers. In mdx mice quadriceps, iNOS expression was mainly observed in regenerating muscle fibers, but not prior to 4 weeks postnatal, and was still present 8 weeks after birth. The expression of dystrophin and the overexpression of utrophin using adenovirus-mediated constructs reduced the number of iNOS-positive fibers in mdx quadriceps muscles. The correction of some pathology in mdx by dystrophin expression or utrophin overexpression was independent of the presence of nNOS. Conclusions: These results suggest that iNOS could play a role in the physiopathology of DMD and that the abnormal expression of iNOS could be corrected by gene therapy.
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页码:355 / 364
页数:10
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