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Vascular endothelial dysfunction in Duchenne muscular dystrophy is restored by bradykinin through upregulation of eNOS and nNOS

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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.

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Acknowledgments

We are grateful to Dr. Jean-Paul Vilaine, Dr Nicole Villeneuve, Dr Marie-Pierre Bourguignon and Dr Willy Gosgnach for their fruitful discussion and for the measurement of cGMP. This study was supported by Association Française contre les Myopathies JBS and LH No. 13031, and SB No. 13802, 14389, 15208 and by the Ministère de l’Agriculture et de l’Alimentation (France).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. INSERM U955, 94000, Créteil, France

    Hubert Dabiré, Lucien Sambin, Carolina Carlos Sampedrano, Vassiliki Gouni, Bijan Ghaleh, Alain Bizé, Jean-Louis Pouchelon, Alain Berdeaux, Luc Hittinger, Valérie Chetboul & Jin Bo Su

  2. UPR de Neurobiologie, Ecole Nationale Vétérinaire d’Alfort, 94700, Maisons-Alfort, France

    Inès Barthélémy, Nicolas Blanchard-Gutton, Yves Unterfinger, Pablo Aguilar, Jean-Laurent Thibaud & Stéphane Blot

  3. Université Paris-Est, 94000, Créteil, France

    Inès Barthélémy, Nicolas Blanchard-Gutton, Yves Unterfinger, Pablo Aguilar, Jean-Laurent Thibaud, Bijan Ghaleh, Alain Bizé, Jean-Louis Pouchelon, Stéphane Blot, Alain Berdeaux, Luc Hittinger & Valérie Chetboul

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Dabiré, H., Barthélémy, I., Blanchard-Gutton, N. et al. Vascular endothelial dysfunction in Duchenne muscular dystrophy is restored by bradykinin through upregulation of eNOS and nNOS. Basic Res Cardiol 107, 240 (2012). https://doi.org/10.1007/s00395-011-0240-6

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