Increased SERCA2a sub-cellular heterogeneity in right-ventricular heart failure inhibits excitation-contraction coupling and modulates arrhythmogenic dynamics.
Increased SERCA2a sub-cellular heterogeneity in right-ventricular heart failure inhibits excitation-contraction coupling and modulates arrhythmogenic dynamics.
复制标题
DOI：
10.1098/rstb.2021.0317
复制
发表时间：
2022-11-21
影响因子：
6.3
通讯作者：
Colman, M. A.
中科院分区：
文献类型：
--
作者：
Holmes, M.;Hurley, M. E.;Sheard, T. M. D.;Benson, A. P.;Jayasinghe, I.;Colman, M. A.
心肌细胞的细胞内钙处理系统负责控制兴奋-收缩偶联（ECC），并且已经与诸如心力衰竭（HF）的病症中的促促心律失常细胞现象相关联。负责细胞内摄取的SERCA2a是钙稳态的主要调节剂，并且其功能的重塑已被提出为疾病中细胞和组织功能障碍的潜在原因。尽管先前已经在多种疾病的背景下研究了对SERCA2a的全局（即全细胞）表达的适应，但其空间分布在亚细胞体积中的作用尚未阐明。我们提出了一种方法来表征SERCA2a的亚细胞异质性，并应用这种方法来量化与右心室（RV）-HF相关的异质性长度尺度（表达相关的距离）的适应。这些表征通知模拟预测功能的影响，这种异质性，其在疾病中的重塑，ECC，钙瞬态交替的动态和自发触发活动的出现。图像分析表明，RV-HF与长度尺度及其细胞间变异性的增加有关;模拟预测，长度尺度的增加可以减少ECC，并严重调节交替和触发活动的脆弱性。这篇文章是“心肌细胞：关于生长，健康和疾病中结构和功能之间相互作用的新启示”主题的一部分。
The intracellular calcium handling system of cardiomyocytes is responsible for controlling excitation-contraction coupling (ECC) and has been linked to pro-arrhythmogenic cellular phenomena in conditions such as heart failure (HF). SERCA2a, responsible for intracellular uptake, is a primary regulator of calcium homeostasis, and remodelling of its function has been proposed as a causal factor underlying cellular and tissue dysfunction in disease. Whereas adaptations to the global (i.e. whole-cell) expression of SERCA2a have been previously investigated in the context of multiple diseases, the role of its spatial profile in the sub-cellular volume has yet to be elucidated. We present an approach to characterize the sub-cellular heterogeneity of SERCA2a and apply this approach to quantify adaptations to the length-scale of heterogeneity (the distance over which expression is correlated) associated with right-ventricular (RV)-HF. These characterizations informed simulations to predict the functional implications of this heterogeneity, and its remodelling in disease, on ECC, the dynamics of calcium-transient alternans and the emergence of spontaneous triggered activity. Image analysis reveals that RV-HF is associated with an increase in length-scale and its inter-cellular variability; simulations predict that this increase in length-scale can reduce ECC and critically modulate the vulnerability to both alternans and triggered activity. This article is part of the theme issue ‘The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease’.
登录
查看更多内容
A型层固定表达的丧失会损害导致肌营养不良症的核隐膜完整性。
影响因子：
7.8
作者：
Sullivan, T;Escalante-Alcalde, D;Bhatt, H;Anver, M;Bhat, N;Nagashima, K;Stewart, C L;Burke, B
通讯作者：
Burke, B
影响因子：
7.8
作者：
GROVE, BK;KURER, V;EPPENBERGER, HM
通讯作者：
EPPENBERGER, HM
影响因子：
3.3
作者：
Barrowman, Jemima;Hamblet, Corinne;Michaelis, Susan
通讯作者：
Michaelis, Susan
影响因子：
56.9
作者：
Fong, LG;Frost, D;Young, SG
通讯作者：
Young, SG
影响因子：
2.9
作者：
YAFFE, D;SAXEL, O
通讯作者：
SAXEL, O