Stretch-induced sarcoplasmic reticulum calcium leak is causatively associated with atrial fibrillation in pressure-overloaded hearts
Stretch-induced sarcoplasmic reticulum calcium leak is causatively associated with atrial fibrillation in pressure-overloaded hearts
复制标题
牵张引起的肌浆网钙渗漏与压力超载心脏中的心房颤动有因果关系
DOI：
10.1093/cvr/cvaa163
复制
发表时间：
2021-04-01
影响因子：
10.8
通讯作者：
Xie, Wenjun
中科院分区：
文献类型：
--
作者：
Zhang, Yi;Qi, Ying;Xie, Wenjun
### 研究目的
尽管有大量报告表明高血压在心房颤动（房颤）的发生发展中起着重要作用，但这一病理过程背后的详细机制仍未完全明确。在此，我们旨在验证以下假设：左心房（LA）压力升高导致的机械牵张引起心房肌细胞舒张期肌浆网（SR）钙离子渗漏，在压力负荷过重心脏的房颤发生过程中起着关键作用。
### 方法与结果
对分离的小鼠心房肌细胞进行急性轴向牵张处理后，肌浆网钙离子渗漏立即增加。我们利用主动脉缩窄（TAC）小鼠模型，进一步探究牵张、肌浆网钙离子渗漏与房颤易感性之间的关系。在TAC术后36小时，来自左心房（承受血流动力学压力）的心肌细胞肌浆网钙离子渗漏显著增加，而右心房（未承受血流动力学压力）的心肌细胞则无此变化，且在TAC术后4周，左心房心肌细胞的肌浆网钙离子渗漏进一步升高。相应地，TAC术后4周的小鼠对心房猝发刺激诱发房颤的易感性也显著增加，而通过敲除半乳糖凝集素 - 3抑制心房纤维化或炎症对这种易感性并无影响。蛋白质免疫印迹分析显示，由于Nox2和Nox4的激活及上调，TAC小鼠左心房肌细胞中的2型兰尼碱受体（RyR2）发生了氧化。使用丹曲林或Rycal S107直接纠正功能异常的RyR2，可减少左心房肌细胞舒张期肌浆网钙离子渗漏，并预防心房猝发刺激诱发的房颤。
### 结论
我们的研究首次证明，左心房肌细胞中氧化应激增强介导的肌浆网钙离子渗漏增加，与压力负荷过重心脏较高的房颤易感性存在因果关系。[图表]
AIMS
Despite numerous reports documenting an important role of hypertension in the development of atrial fibrillation (AF), the detailed mechanism underlying the pathological process remains incompletely understood. Here, we aim to test the hypothesis that diastolic sarcoplasmic reticulum (SR) Ca2+ leak in atrial myocytes, induced by mechanical stretch due to elevated pressure in the left atrium (LA), plays an essential role in the AF development in pressure-overloaded hearts.
METHODS AND RESULTS
Isolated mouse atrial myocytes subjected to acute axial stretch displayed an immediate elevation of SR Ca2+ leak. Using a mouse model of transverse aortic constriction (TAC), the relation between stretch, SR Ca2+ leak and AF susceptibility was further tested. At 36 hours post TAC, SR Ca2+ leak in cardiomyocytes from the LA (with hemodynamic stress), but not right atrium (without hemodynamic stress), significantly increased, which was further elevated at 4 weeks post TAC. Accordingly, AF susceptibility to atrial burst pacing in the 4-week TAC mice were also significantly increased, which was unaffected by inhibition of atrial fibrosis or inflammation via deletion of galectin-3. Western blotting revealed that type 2 ryanodine receptor (RyR2) in LA myocytes of TAC mice was oxidized due to activation and upregulation of Nox2 and Nox4. Direct rescue of dysfunctional RyR2 with dantrolene or rycal S107 reduced diastolic SR Ca2+ leak in LA myocytes and prevented atrial burst pacing stimulated AF.
CONCLUSION
Our study demonstrated for the first time the increased SR Ca2+ leak mediated by enhanced oxidative stress in LA myocytes that is causatively associated with higher AF susceptibility in pressure-overloaded hearts.
TRANSLATIONAL PERSPECTIVE
RyR2 is the major Ca2+ channel in cardiac myocytes, strongly affecting cellular activities. Several types of heart diseases, including heart failure and ventricular arrhythmias, are related to RyR2 dysfunction in ventricular myocytes. The present study expands RyR2 dysfunction as a critical contributor in pressure-overload associated AF. As AF is usually accompanied with cardiac remodeling and dysfunction in the setting of hypertension, which is a common risk factor for different cardiovascular diseases, the convergence of several pathological processes on the dysfunctional RyR2 makes it a common therapeutic target in these diseased settings.