Ventricular
arrhythmia is one of the main causes of
sudden cardiac death, especially after
myocardial ischemia. Previous studies have shown that Chai-Hu-San-Shen
capsule (CHSSC) can reduce the incidence of ventricular arrhythmias following
myocardial ischemia, however, the mechanisms of it are unclear. In present study, we explored the mechanism of CHSSC ameliorates ventricular
arrhythmia following
myocardial ischemia via inhibiting the
CaMKII/
FKBP12.6/
RyR2/Ca2+ signaling pathway. In vivo, a
myocardial ischemia rat model was established and treated with CHSSC to evaluate the
therapeutic effect of CHSSC. In vitro, we established an
ischemia model in H9C2 cells and treated with CHSSC,
KN-93, or
H-89. Then, intracellular Ca2+ content, the expression of
RyR2, and the interaction between
FKBP12.6 and
RyR2 were detected. The results showed that CHSSC could delay the occurrence of ventricular arrhythmias and shorten the duration of ventricular arrhythmias. After
myocardial ischemia, the intracellular Ca2+ content was increased, and CHSSC treatment mitigated this increase, down-regulated the levels of p-
CaMKII,
CaMKII, p-RyR2, and
RyR2, and up-regulated the levels of p-RyR2 (Ser2808) and p-RyR2 (Ser2814). Co-immunoprecipitation showed an interaction between
FKBP12.6 and
RyR2, and CHSSC up-regulated the content of the FKBP12.6-RyR2 complex in ischemic cells. In conclusion, our study showed that
CaMKII activation led to hyperphosphorylation of
RyR2 (Ser2814) and
RyR2 (Ser2808) during cardiomyocyte
ischemia, which resulted in dissociation of the FKBP12.6-RyR2 complex, and increased intracellular Ca2+ content, which may contribute to the development of ventricular arrhythmias. CHSSC may reduce the incidence of ventricular arrhythmias following
myocardial ischemia through inhibition of the
CaMKII/
RyR2/
FKBP12.6/Ca2+ signaling pathway.