Résumé :
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Mutations in dystrophin gene result in loss of dystrophin protein in striated muscles leading to Duchenne muscular dystrophy (DMD) that remains an untreatable disease.Similarly, due to a mutation of the dystrophin gene leading to loss of the protein in striated muscles, GRMD (Golden retriever muscular dystrophy) dogs reproduce thepathology and clinical symptoms of the human DMD. A previous study has shown that chronic bradykinin (BK) infusion prevents the progression of heart failure inducedby rapid pacing in dogs. In the present study, we examined the effects of chronic BK infusion on left ventricular (LV) function in GRMD dogs with reduced fractionalshortening (28±2% vs 38±2% in GRMD and control dogs, respectively; p<0.001) and impaired endo-epicardial gradient of radial systolic velocity (1.3±0.1 cm/s vs3.8±0.2 cm/s in GRMD and control dogs, respectively; p<0.001) measured by echocardiography. BK infusion (1 ?g/min, 4 weeks) restored these parameters to levelssimilar to those measured in control animals. The tension-pCa relationships established at 2 sarcomere lengths in isolated permeabilized subendocardial cells wereshifted along the pCa axis toward higher Ca2+ concentrations in placebo-treated GRMD dogs compared to control myocytes. This was associated with a reduction inmaximal tension and a change in Ca2+ sensitivity in subendocardial cells leading to loss of the endo-epicardial gradient of myofilament length-dependent activation. Adecreased cardiac myosin-binding protein C phosphorylation and an increased troponin-I phosphorylation were observed in the subendocardial myocytes of placebotreatedGRMD dogs. These changes were normalized in BK-treated GRMD dogs compared to control animals. In addition, the endothelial nitric oxide synthase (eNOS)levels in LV subendocardial and subepicardial regions were reduced in placebo-treated GRMD dogs while those of BK-treated GRMD dogs were similar to control dogs.Thus, chronic administration of BK normalizes LV contractile function in GRMD dogs by restoring the endo-epicardial gradient of myofilament length-dependent activation,the eNOS expression and the sarcomeric protein phosphorylation. These data suggest that sarcomeric protein phosphorylation and NOS expression in the myocardiumare the potential targets to treat cardiomyopathy in DMD patients
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