title: Vascular endothelial dysfunction in Duchenne muscular dystrophy is restored by bradykinin through upregulation of eNOS and nNOS.
abstract: Little is known about the vascular function and expression of endothelial and neuronal nitric oxide synthases (eNOS and nNOS) in Duchenne muscular dystrophy (DMD). Bradykinin is involved in the regulation of eNOS expression induced by angiotensin-converting enzyme inhibitors. We characterized the vascular function and eNOS and nNOS expression in a canine model of DMD and evaluated the effects of chronic bradykinin treatment. Vascular function was examined in conscious golden retriever muscular dystrophy (GRMD) dogs with left ventricular dysfunction (measured by echocardiography) and in isolated coronary arteries. eNOS and nNOS proteins in carotid arteries were measured by western blot and cyclic guanosine monophosphate (cGMP) content was analyzed by radioimmunoassay. Compared with controls, GRMD dogs had an impaired vasodilator response to acetylcholine. In isolated coronary artery, acetylcholine-elicited relaxation was nearly absent in placebo-treated GRMD dogs. This was explained by reduced nNOS and eNOS proteins and cGMP content in arterial tissues. Chronic bradykinin infusion (1 μg/min, 4 weeks) restored in vivo and in vitro vascular response to acetylcholine to the level of control dogs. This effect was NO-mediated through upregulation of eNOS and nNOS expression. In conclusion, this study is the first to demonstrate that DMD is associated with NO-mediated vascular endothelial dysfunction linked to an altered expression of eNOS and nNOS, which can be overcome by bradykinin.
authors.affiliation: INSERM U955, 94000, Créteil, France.
authors.forename: Hubert
authors.initials: H
authors.lastname: Dabiré
authors.forename: Inès
authors.initials: I
authors.lastname: Barthélémy
authors.forename: Nicolas
authors.initials: N
authors.lastname: Blanchard-Gutton
authors.forename: Lucien
authors.initials: L
authors.lastname: Sambin
authors.forename: Carolina Carlos
authors.initials: CC
authors.lastname: Sampedrano
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Gouni
authors.forename: Yves
authors.initials: Y
authors.lastname: Unterfinger
authors.forename: Pablo
authors.initials: P
authors.lastname: Aguilar
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Thibaud
authors.forename: Bijan
authors.initials: B
authors.lastname: Ghaleh
authors.forename: Alain
authors.initials: A
authors.lastname: Bizé
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Pouchelon
authors.forename: Stéphane
authors.initials: S
authors.lastname: Blot
authors.forename: Alain
authors.initials: A
authors.lastname: Berdeaux
authors.forename: Luc
authors.initials: L
authors.lastname: Hittinger
authors.forename: Valérie
authors.initials: V
authors.lastname: Chetboul
authors.forename: Jin Bo
authors.initials: JB
authors.lastname: Su
mesh_terms: D000818:Animals; D001794:Blood Pressure; D001920:Bradykinin / Q000502:physiology*; D002339:Carotid Arteries / Q000201:enzymology; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D004730:Endothelium, Vascular / Q000503:physiopathology*; D020388:Muscular Dystrophy, Duchenne / Q000201:enzymology / Q000503:physiopathology*; D009569:Nitric Oxide / Q000502:physiology; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left
chemical_list: D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D006152:Cyclic GMP; D001920:Bradykinin