title: Smooth muscle-specific dystrophin expression improves aberrant vasoregulation in mdx mice.
abstract: 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 alpha-adrenergic vasoregulation in the 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 that express dystrophin only in smooth muscle (SMTg/mdx). We found that alpha-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 alpha-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.
authors.affiliation: Department of Child Development, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University Graduate School, Kumamoto 860-0811, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Ito
authors.forename: Shigemi
authors.initials: S
authors.lastname: Kimura
authors.forename: Shiro
authors.initials: S
authors.lastname: Ozasa
authors.forename: Makoto
authors.initials: M
authors.lastname: Matsukura
authors.forename: Makoto
authors.initials: M
authors.lastname: Ikezawa
authors.forename: Kowashi
authors.initials: K
authors.lastname: Yoshioka
authors.forename: Hiroe
authors.initials: H
authors.lastname: Ueno
authors.forename: Misao
authors.initials: M
authors.lastname: Suzuki
authors.forename: Kimi
authors.initials: K
authors.lastname: Araki
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yamamura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miwa
authors.forename: George
authors.initials: G
authors.lastname: Dickson
authors.forename: Gail D
authors.initials: GD
authors.lastname: Thomas
authors.forename: Teruhisa
authors.initials: T
authors.lastname: Miike
mesh_terms: D000818:Animals; D001483:Base Sequence; D003402:Creatine Kinase / Q000097:blood; D018076:DNA, Complementary / Q000235:genetics; D016189:Dystrophin / Q000235:genetics* / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000098:blood supply / Q000503:physiopathology*; D009137:Muscular Dystrophy, Animal / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000503:physiopathology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011942:Receptors, Adrenergic, alpha / Q000502:physiology; D014661:Vasoconstriction
chemical_list: D018076:DNA, Complementary; D016189:Dystrophin; D011942:Receptors, Adrenergic, alpha; D019001:Nitric Oxide Synthase; D003402:Creatine Kinase