Abstract
Cardiac troponin T (cTnT) mutations that increase myofilament Ca2+ sensitivity cause Familial Hypertrophic Cardiomyopathy (FHC), which leads to sudden cardiac death. However, the underlying mechanism by which the cTnT mutations lead to lethal arrhythmia remains elusive. Here, we investigated the pathogenic role of phosphorylation-mediated aberrant Ca2+ release via cardiac ryanodine receptor (RyR2) and therapeutic effects of dantrolene, which was found to correct interdomain interactions of RyR2, in transgenic mouse (TG) model with FHC-related cTnT mutation (TNT-delta160E). In 6-months-old TG, there was no appreciable difference in hearts, compared with non-TG. In response to isoproterenol (ISO 10nmol/L), the Ca2+ spark frequency (SpF) and spontaneous Ca2+ transient (sCaT) after 5Hz pacing were much higher in TG cardiomyocytes (ISO-TG) than in non-TG cardiomyocytes (Non-TG). It was largely reversed by CaMKII inhibitor (KN-93) but not by PKA inhibitor. These abnormal events in ISO-TG were reproduced by adding EGTA-AM into ISO-treated Non-TG, suggesting that increased Ca2+ buffering capacity, causing an increase in diastolic [Ca2+], may predispose to aberrant Ca2+ release events. Moreover, dantrolene attenuated ISO-induced SpF, time from peak to 70% decline of Ca2+ transient and sCaT in TG cardiomyocytes. In FHC-linked cTnT-mutated hearts, RyR2 stabilization by inhibiting aberrant Ca2+ release mediated by CaMKII signaling and Ca2+buffering function might be a new therapeutic target for preventing the development of arrhythmias in FHC. Cardiac troponin T (cTnT) mutations that increase myofilament Ca2+ sensitivity cause Familial Hypertrophic Cardiomyopathy (FHC), which leads to sudden cardiac death. However, the underlying mechanism by which the cTnT mutations lead to lethal arrhythmia remains elusive. Here, we investigated the pathogenic role of phosphorylation-mediated aberrant Ca2+ release via cardiac ryanodine receptor (RyR2) and therapeutic effects of dantrolene, which was found to correct interdomain interactions of RyR2, in transgenic mouse (TG) model with FHC-related cTnT mutation (TNT-delta160E). In 6-months-old TG, there was no appreciable difference in hearts, compared with non-TG. In response to isoproterenol (ISO 10nmol/L), the Ca2+ spark frequency (SpF) and spontaneous Ca2+ transient (sCaT) after 5Hz pacing were much higher in TG cardiomyocytes (ISO-TG) than in non-TG cardiomyocytes (Non-TG). It was largely reversed by CaMKII inhibitor (KN-93) but not by PKA inhibitor. These abnormal events in ISO-TG were reproduced by adding EGTA-AM into ISO-treated Non-TG, suggesting that increased Ca2+ buffering capacity, causing an increase in diastolic [Ca2+], may predispose to aberrant Ca2+ release events. Moreover, dantrolene attenuated ISO-induced SpF, time from peak to 70% decline of Ca2+ transient and sCaT in TG cardiomyocytes. In FHC-linked cTnT-mutated hearts, RyR2 stabilization by inhibiting aberrant Ca2+ release mediated by CaMKII signaling and Ca2+buffering function might be a new therapeutic target for preventing the development of arrhythmias in FHC.
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