Leaky RyR2 trigger ventricular arrhythmias in Duchenne muscular dystrophy
J Fauconnier, J Thireau, S Reiken… - Proceedings of the …, 2010 - National Acad Sciences
Proceedings of the National Academy of Sciences, 2010•National Acad Sciences
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) Ca2+ release
channel/ryanodine receptor (RyR2) occurs in the mdx mouse model of DMD. RyR2 from …
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) Ca2+ release
channel/ryanodine receptor (RyR2) occurs in the mdx mouse model of DMD. RyR2 from …
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) Ca2+ 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 Ca2+ leak. Inhibiting the depletion of calstabin2 from the RyR2 complex with the Ca2+ channel stabilizer S107 (“rycal”) inhibited the SR Ca2+ leak, inhibited aberrant depolarization in isolated cardiomyocytes, and prevented arrhythmias in vivo. This suggests that diastolic SR Ca2+ 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 Ca2+ leak prevents fatal sudden cardiac arrhythmias in DMD.
National Acad Sciences
以上显示的是最相近的搜索结果。 查看全部搜索结果