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Leaky RyR2 trigger ventricular arrhythmias in Duchenne muscular dystrophy.

Fauconnier, Jérémy; Thireau, Jérôme; Reiken, Steven; Cassan, Cécile; Richard, Sylvain; Matecki, Stefan; Marks, Andrew R; Lacampagne, Alain.
Proc Natl Acad Sci U S A; 107(4): 1559-64, 2010 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-20080623
Patients with Duchenne muscular dystrophy (DMD) have a progressive dilated cardiomyopathy associated with fatal cardiac arrhythmias. Electrical and functional abnormalities have been attributed to cardiac fibrosis; however, electrical abnormalities may occur in the absence of overt cardiac histopathology. Here we show that structural and functional remodeling of the cardiac sarcoplasmic reticulum (SR) Ca(2+) release channel/ryanodine receptor (RyR2) occurs in the mdx mouse model of DMD. RyR2 from mdx hearts were S-nitrosylated and depleted of calstabin2 (FKBP12.6), resulting in "leaky" RyR2 channels and a diastolic SR Ca(2+) leak. Inhibiting the depletion of calstabin2 from the RyR2 complex with the Ca(2+) channel stabilizer S107 ("rycal") inhibited the SR Ca(2+) leak, inhibited aberrant depolarization in isolated cardiomyocytes, and prevented arrhythmias in vivo. This suggests that diastolic SR Ca(2+) leak via RyR2 due to S-nitrosylation of the channel and calstabin2 depletion from the channel complex likely triggers cardiac arrhythmias. Normalization of the RyR2-mediated diastolic SR Ca(2+) leak prevents fatal sudden cardiac arrhythmias in DMD.
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