Stabilizing cardiac ryanodine receptor with dantrolene treatment prevents left ventricular remodeling in pressure-overloaded heart failure mice
Stabilizing cardiac ryanodine receptor with dantrolene treatment prevents left ventricular remodeling in pressure-overloaded heart failure mice
复制标题
用丹曲林治疗稳定心脏兰尼碱受体可预防压力超负荷心力衰竭小鼠的左心室重构
DOI：
10.1016/j.bbrc.2022.12.063
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发表时间：
2023
影响因子：
3.1
通讯作者：
Yano Masafumi
中科院分区：
文献类型：
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作者：
Yano Yasutake;Kobayashi Shigeki;Uchida Tomoyuki;Chang Yaowei;Nawata Junya;Fujii Shohei;Nakamura Yoshihide;Suetomi Takeshi;Uchinoumi Hitoshi;Oda Tetsuro;Yamamoto Takeshi;Yano Masafumi
丹曲林（DAN）通过N端结构域的Leu 601-Cys 620直接与心脏Ryanodine受体2（RyR 2）结合，随后通过RyR 2抑制舒张期Ca 2+渗漏。我们先前报道了使用RyR 2 V3599 K突变的治疗，该突变通过增强钙调蛋白（CaM）与RyR 2的结合能力来抑制舒张期Ca 2+渗漏，从而防止了横向主动脉缩窄（TAC）心力衰竭中的左心室（LV）重构。在这里，我们研究了DAN的长期管理是否通过遗传治疗相同的机制，防止左心室重构在TAC心力衰竭。使用TAC建立压力超负荷肥大小鼠模型。将野生型（WT）小鼠分为三组：假手术小鼠（Sham组）、TAC小鼠（TAC组）和用DAN处理的TAC小鼠（TAC-DAN组，20 mg/kg/天，腹膜内）。然后随访8周。TAC-DAN组的存活率（83%）高于TAC组（49%），系列超声心动图研究和病理组织分析显示，与TAC组相比，TAC-DAN组显著预防了LV重构。在TAC组中，舒张期Ca 2+火花频率增加，CaM与RyR 2的结合亲和力降低，但在TAC-DAN组中没有观察到。DAN稳定RyR 2可通过增强CaM与RyR 2的结合并抑制RyR 2介导的舒张期Ca 2+渗漏来预防LV重构并改善TAC后的存活率。
Dantrolene (DAN) directly binds to cardiac ryanodine receptor 2 (RyR2) through Leu601–Cys620in the N-terminal domain and subsequently inhibits diastolic Ca2+leakage through RyR2. We previously reported that therapy using RyR2 V3599K mutation, which inhibits diastolic Ca2+leakage by enhancing calmodulin (CaM) binding ability to RyR2, prevents left ventricular (LV) remodeling in transverse aortic constriction (TAC) heart failure. Here, we examined whether chronic administration of DAN prevents LV remodeling in TAC heart failure via the same mechanism as genetic therapy. A pressure-overloaded hypertrophy mouse model was developed using TAC. Wild-type (WT) mice were divided into three groups: sham-operated mice (Sham group), TAC mice (TAC group), and TAC mice treated with DAN (TAC-DAN group, 20 mg/kg/day, i.p.). They were then followed up for 8 weeks. The survival rate was higher in the TAC-DAN group (83%) than in the TAC group (49%), and serial echocardiography studies and pathological tissue analysis showed that LV remodeling was significantly prevented in the TAC-DAN group compared to the TAC group. An increase in the diastolic Ca2+spark frequency and a decrease in the binding affinity of CaM to RyR2 were observed at 8 weeks in the TAC group but not in the TAC-DAN group. Stabilization of RyR2 with DAN prevented LV remodeling and improved survival after TAC by enhancing CaM binding to RyR2 and inhibiting RyR2-mediated diastolic Ca2+leakage.