title: Bradykinin restores left ventricular function, sarcomeric protein phosphorylation, and e/nNOS levels in dogs with Duchenne muscular dystrophy cardiomyopathy.
abstract: OBJECTIVE
  Cardiomyopathy is a lethal result of Duchenne muscular dystrophy (DMD), but its characteristics remain elusive. The golden retriever muscular dystrophy (GRMD) dogs produce DMD pathology and mirror DMD patient's symptoms, including cardiomyopathy. We previously showed that bradykinin slows the development of pacing-induced heart failure. Therefore, the goals of this research were to characterize dystrophin-deficiency cardiomyopathy and to examine cardiac effects of bradykinin in GRMD dogs.
  
  
  RESULTS
  At baseline, adult GRMD dogs had reduced fractional shortening (28 ± 2 vs. 38 ± 2% in control dogs, P < 0.001) and left ventricular (LV) subendocardial dysfunction leading to impaired endo-epicardial gradient of radial systolic velocity (1.3 ± 0.1 vs. 3.8 ± 0.2 cm/s in control dogs, P < 0.001) measured by echocardiography. These changes were normalized by bradykinin infusion (1 µg/min, 4 weeks). In isolated permeabilized LV subendocardial cells of GRMD dogs, tension-calcium relationships were shifted downward and force-generating capacity and transmural gradient of myofilament length-dependent activation were impaired compared with control dogs. Concomitantly, phosphorylation of sarcomeric regulatory proteins and levels of endothelial and neuronal nitric oxide synthase (e/nNOS) in LV myocardium were significantly altered in GRMD dogs. All these abnormalities were normalized in bradykinin-treated GRMD dogs.
  
  
  CONCLUSIONS
  Cardiomyopathy in GRMD dogs is characterized by profound LV subendocardial dysfunction, abnormal sarcomeric protein phosphorylation, and impaired e/nNOS, which can be normalized by bradykinin treatment. These data provide new insights into the pathophysiological mechanisms accounting for DMD cardiomyopathy and open new therapeutic perspectives.
authors.affiliation: INSERM U955, ENVA, 7 avenu du Général de Gaulle, Maisons-Alfort, France. jin-bo.su@inserm.fr
authors.forename: Jin Bo
authors.initials: JB
authors.lastname: Su
authors.forename: Olivier
authors.initials: O
authors.lastname: Cazorla
authors.forename: Stéphane
authors.initials: S
authors.lastname: Blot
authors.forename: Nicolas
authors.initials: N
authors.lastname: Blanchard-Gutton
authors.forename: Younss
authors.initials: Y
authors.lastname: Ait Mou
authors.forename: Inès
authors.initials: I
authors.lastname: Barthélémy
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: Alain
authors.initials: A
authors.lastname: Bizé
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Pouchelon
authors.forename: Hubert
authors.initials: H
authors.lastname: Dabiré
authors.forename: Bijan
authors.initials: B
authors.lastname: Ghaleh
authors.forename: Alain
authors.initials: A
authors.lastname: Berdeaux
authors.forename: Valérie
authors.initials: V
authors.lastname: Chetboul
authors.forename: Alain
authors.initials: A
authors.lastname: Lacampagne
authors.forename: Luc
authors.initials: L
authors.lastname: Hittinger
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D004285:Dogs; D020388:Muscular Dystrophy, Duchenne / Q000503:physiopathology*; D009200:Myocardial Contraction / Q000187:drug effects; D052248:Nitric Oxide Synthase Type I / Q000032:analysis / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000032:analysis / Q000502:physiology*; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism*; D012518:Sarcomeres / Q000378:metabolism*; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D011506:Proteins; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D001920:Bradykinin