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keywordcardiac hypertrophy resource typedepartmental bulletin paper
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Cardiac hypertrophy is widely recognized as a significant risk factor contributing to adverse outcomes in individuals with cardiovascular conditions. The disruption of intracellular calcium ( Ca^{2+} ) balance has been implicated in the development of cardiac hypertrophy, though the precise mechanisms remain poorly understood. In this research, we explored whether hypertrophy induced by pressure overload may arise from the destabilization of the cardiac ryanodine receptor (RyR2) triggered by the dissociation of calmodulin (CaM), leading to subsequent Ca^{2+} leakage. We also assessed whether genetically strengthening the binding affinity between CaM and RyR2 could potentially reverse this process. In the early phases of cardiac hypertrophy caused by pressure overload—when contractile function is still intact—we observed that RyR2 destabilization mediated by reactive oxygen species (ROS) coincides with impaired relaxation. Moreover, stabilizing RyR2 through enhanced CaM binding was found to completely inhibit hypertrophic signaling and improve survival rates. Our findings reveal a crucial connection between RyR2 destabilization and the progression of cardiac hypertrophy.
Creators : Kohno Michiaki | Kobayashi Shigeki | Yamamoto Takeshi | Yano Masafumi Publishers : Yamaguchi University School of Medicine Date Issued : 2025-06
To investigate whether dantrolene (DAN), cardiac ryanodine receptor (RyR2) stabilizer, improves impaired diastolic function in an early pressure-overloaded hypertrophied heart, pressure-overload hypertrophy was induced by transverse aortic constriction (TAC) in mice. Wild-type (WT) mice were divided into four groups: sham-operated mice (Sham), sham-operated mice treated with DAN (DAN+Sham), TAC mice (TAC), and TAC mice treated with DAN (DAN+TAC). The mice were then followed up for 2 weeks. Left ventricular (LV) hypertrophy was induced in TAC, but not DAN+TAC mice, 2 weeks after TAC. There were no differences in LV fractional shortening among the four groups. Catheter tip micromanometer showed that the time constant of LV pressure decay, an index of diastolic function, was significantly prolonged in TAC but not in DAN+TAC mice. Diastolic function was significantly impaired in TAC, but not in DAN+TAC mice as determined by cell shortening and Ca^{2+} transients. An increase in diastolic Ca^{2+} leakage and a decrease in calmodulin (CaM) binding affinity to RyR2 were observed in TAC mice, while diastolic Ca^{2+} leakage improved in DAN+TAC mice. Thus, DAN prevented the progression of hypertrophy and improved the impairment of LV relaxation by inhibiting diastolic Ca^{2+} leakage through RyR2 and the dissociation of CaM from RyR2.
Creators : Chang Yaowei | Kobayashi Shigeki | Yano Yasutake | Uchida Tomoyuki | Nawata Junya | Fujii Shohei | Nakamura Yoshihide | Suetomi Takeshi | Uchinoumi Hitoshi | Oda Tetsuro | Yamamoto Takeshi | Yano Masafumi Publishers : Yamaguchi University School of Medicine Date Issued : 2023-06