Human Molecular Genetics Advance Access published online on June 15, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl151
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1 Department of Child Development, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University Graduate School, Kumamoto 860-0811, Japan; Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082, Japan
* To whom correspondence should be addressed. Duchenne muscular dystrophy (DMD) is a fatal X-linked muscle wasting disease caused by mutations of the gene encoding the cytoskeletal protein dystrophin. Therapeutic options for DMD are limited because the pathogenetic mechanism by which dystrophin deficiency produces the clinical phenotype remains obscure. Recent reports of abnormal ?-adrenergic vasoregulation in exercising muscles of DMD patients and in the mdx mouse, an animal model of DMD, prompted us to hypothesize that the dystrophin-deficient smooth muscle contributes to the vascular and dystrophic phenotypes of DMD. To test this, we generated transgenic mdx mice which express dystrophin only in smooth muscle (SMTg/mdx). We found that
Received March 1, 2006
Revised June 7, 2006
Accepted June 7, 2006
Article
Smooth muscle-specific dystrophin expression improves aberrant vasoregulation in mdx mice
Kaori Ito 1,
Shigemi Kimura 2 *,
Shiro Ozasa 3,
Makoto Matsukura 1,
Makoto Ikezawa 3,
Kowashi Yoshioka 3,
Hiroe Ueno 3,
Misao Suzuki 4,
Kimi Araki 5,
Ken-ichi Yamamura 5,
Takeshi Miwa 6,
George Dickson 7,
Gail D. Thomas 8,
and
Teruhisa Miike 3
2 Department of Child Development, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University Graduate School, 1-1-1 Honjou Kumamoto 860-0811, Japan
3 Department of Child Development, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University Graduate School, Kumamoto 860-0811, Japan
4 Division of Transgenic Technology Center for Animal Resource and Development, Kumamoto University Graduate School, Kumamoto 860-0811, Japan
5 Division of Developmental Genetics, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan
6 Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
7 Centre for Biomedical Sciences, Royal Holloway University of London, Egham, Surrey, TW20 0EX, UK
8 Division of Hypertension, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA
Shigemi Kimura, E-mail: kimusige{at}kaiju.medic.kumamoto-u.ac.jp
Abstract 
-adrenergic vasoconstriction was markedly attenuated in the contracting hindlimbs of C57BL/10 wild type mice, an effect that was mediated by nitric oxide (NO) and was severely impaired in the mdx mice. SMTg/mdx mice showed an intermediate phenotype, with partial restoration of the NO-dependent modulation of ?-adrenergic vasoconstriction in active muscle. In addition, the elevated serum creatine kinase levels observed in mdx mice were significantly reduced in SMTg/mdx mice. This is the first report of a functional role of dystrophin in vascular smooth muscle.
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