Bradykinin restores left ventricular function, sarcomeric protein phosphorylation, and e/nNOS levels in dogs with Duchenne muscular dystrophy cardiomyopathy

Jin Bo Su, Olivier Cazorla, Stéphane Blot, Nicolas Blanchard-Gutton, Younss Ait Mou, Inès Barthélémy, Lucien Sambin, Carolina Carlos Sampedrano, Vassiliki Gouni, Yves Unterfinger, Pablo Aguilar, Jean Laurent Thibaud, Alain Bizé, Jean Louis Pouchelon, Hubert Dabiré, Bijan Ghaleh, Alain Berdeaux, Valérie Chetboul, Alain Lacampagne, Luc Hittinger

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16 Citations (Scopus)


Aims 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 patients 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. Methods and 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 g/min, 4 weeks). In isolated permeabilized LV subendocardial cells of GRMD dogs, tensioncalcium 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. Conclusion sCardiomyopathy 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. Published on behalf of the European Society of Cardiology. All rights reserved.

Original languageEnglish
Pages (from-to)86-96
Number of pages11
JournalCardiovascular Research
Issue number1
Publication statusPublished - 1 Jul 2012
Externally publishedYes



  • Bradykinin
  • Duchenne muscular dystrophy cardiomyopathy
  • Myofilament Ca sensitivity
  • Nitric oxide synthase
  • Protein phosphorylation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

Cite this

Su, J. B., Cazorla, O., Blot, S., Blanchard-Gutton, N., Mou, Y. A., Barthélémy, I., Sambin, L., Sampedrano, C. C., Gouni, V., Unterfinger, Y., Aguilar, P., Thibaud, J. L., Bizé, A., Pouchelon, J. L., Dabiré, H., Ghaleh, B., Berdeaux, A., Chetboul, V., Lacampagne, A., & Hittinger, L. (2012). Bradykinin restores left ventricular function, sarcomeric protein phosphorylation, and e/nNOS levels in dogs with Duchenne muscular dystrophy cardiomyopathy. Cardiovascular Research, 95(1), 86-96.