Stabilizing ryanodine receptor type 2: a novel strategy for the treatment of atrial fibrillation.
We propose that stabilizing ryanodine receptor type 2 (RyR2) may be a novel strategy for the treatment of atrial fibrillation (AF). Sarcoplasmic reticulum (SR) dysfunction caused by hyperphosphorylation of RyR2 and/or partial depletion of the stabilizing subunit calstabin2 has been indicated in AF. RyR2 stabilization may prevent SR dysfunction and thereby protect the heart from damage. Hypertrophy, hyperthyroidism and heart failure, three common pathological conditions associated with AF, result in increased SR Ca(2+) leak via RyR2. RyR2 stabilization may prevent SR Ca(2+) leak and thereby prevent AF. Triggered activity appears to underlie atrial ectopic foci, which cause AF. Diastolic Ca(2+) leak from SR via RyR2 may initiate triggered activity. Therefore, modulating RyR2 opening probability would be predicted to protect against triggered activity. Atrial oxidative stress plays a contributing role in the pathogenesis of AF. RyR2 is a target of reactive oxygen species, and chronic RyR2 oxidation increases RyR2 opening probability in a more sustained, less reversible manner. Strategies that attenuate oxidative stress and protect against AF may also contribute to RyR2 stabilization. Finally, KN-3 and JTV519, two compounds that stabilize RyR2 in the closed state, prevent the induction of triggered activity and suppress the inducibility of sustained AF. Thus, it is reasonable to speculate that experimental approaches designed to improve RyR2 stabilization will drive a novel conceptual revolution in AF drug development and lead to new clinical investigations.
Cheng
Yan
Y
Department of Psychiatry, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
Zhan
Qin
Q
Zhao
Jiangmin
J
Xiao
Junjie
J
D000818:Animals; D001281:Atrial Fibrillation / Q000628:therapy*; D006801:Humans; D008955:Models, Cardiovascular; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*
D019837:Ryanodine Receptor Calcium Release Channel