RyR2-targeting therapy prevents left ventricular remodeling and ventricular tachycardia in post-infarction heart failure
RyR2-targeting therapy prevents left ventricular remodeling and ventricular tachycardia in post-infarction heart failure
复制标题
RyR2 靶向治疗可预防梗死后心力衰竭中的左心室重构和室性心动过速
DOI：
10.1016/j.yjmcc.2023.03.007
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发表时间：
2023
影响因子：
5
通讯作者：
Yano Masafumi
中科院分区：
文献类型：
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作者：
Fujii Shohei;Kobayashi Shigeki;Chang Yaowei;Nawata Junya;Yoshitomi Ryosuke;Tanaka Shinji;Kohno Michiaki;Nakamura Yoshihide;Ishiguchi Hironori;Suetomi Takeshi;Uchinoumi Hitoshi;Oda Tetsuro;Okuda Shinichi;Okamura Takayuki;Yamamoto Takeshi;Yano Masafumi
丹曲林结合心脏红嘌呤受体（RyR2） n端结构域leu601 - cys620区域，与骨红嘌呤受体leu590 - cys609区域相对应，并通过RyR2抑制舒张期Ca2+渗漏。目的探讨丹曲林对心肌梗死（MI）后左室（LV）重构和室性心动过速（VT）的抑制机制是否与RyR2基因V3599K突变相同，表明丹曲林通过增强钙调蛋白（calmodulin, CaM）与RyR2的结合亲和力来抑制舒张期Ca2+泄漏。方法和结果建立小鼠冠状动脉左前降支结扎心肌梗死模型。野生型（WT）小鼠分为四组：假手术小鼠（WT- sham）、假手术小鼠（WT- sham- dan）、心肌梗死小鼠（WT-MI）和心肌梗死小鼠（WT-MI- dan）。将纯合子V3599K RyR2敲入（KI）小鼠分为假手术小鼠（KI- sham）和心肌梗死小鼠（KI-MI）两组。小鼠随访12周。WT-MI- dan组（73%）和KI-MI组（70%）的生存率明显高于WT-MI组（40%）。超声心动图、病理组织和肾上腺素诱导的室速研究显示，与WT-MI组相比，WT-MI- dan组和KI-MI组的左室重构和室速均被阻止。在心肌梗死后12周，WT-MI组观察到舒张Ca2+火花频率增加，CaM与RyR2结合亲和力降低，尽管在WT-MI- dan和KI-MI组观察到这些值显着改善。结论RyR2四聚体结构的药理学或遗传学稳定可通过抑制左室重构和心律失常原提高心肌梗死后的生存率。
BackgroundDantrolene binds to the Leu601-Cys620region of the N-terminal domain of cardiac ryanodine receptor (RyR2), which corresponds to the Leu590-Cys609region of the skeletal ryanodine receptor, and suppresses diastolic Ca2+leakage through RyR2.ObjectiveWe investigated whether the chronic administration of dantrolene prevented left ventricular (LV) remodeling and ventricular tachycardia (VT) after myocardial infarction (MI) by the same mechanism with the mutation V3599K of RyR2, which indicated that the inhibition of diastolic Ca2+leakage occurred by enhancing the binding affinity of calmodulin (CaM) to RyR2.Methods and resultsA left anterior descending coronary artery ligation MI model was developed in mice. Wild-type (WT) were divided into four groups: sham-operated mice (WT-Sham), sham-operated mice treated with dantrolene (WT-Sham-DAN), MI mice (WT-MI), and MI mice treated with dantrolene (WT-MI-DAN). Homozygous V3599K RyR2 knock-in (KI) mice were divided into two groups: sham-operated mice (KI-Sham) and MI mice (KI-MI). The mice were followed for 12 weeks.Survival was significantly higher in the WT-MI-DAN (73%) and KI-MI groups (70%) than the WT-MI group (40%). Echocardiography, pathological tissue, and epinephrine-induced VT studies showed that LV remodeling and VT were prevented in the WT-MI-DAN and KI-MI groups compared to the WT-MI group. An increase in diastolic Ca2+spark frequency and a decrease in the binding affinity of CaM to the RyR2 were observed at 12 weeks after MI in the WT-MI group, although significant improvements in these values were observed in the WT-MI-DAN and KI-MI groups.ConclusionsPharmacological or genetic stabilization of RyR2 tetrameric structure improves survival after MI by suppressing LV remodeling and proarrhythmia.