RyR2 and Calcium Release in Heart Failure.
RyR2 and Calcium Release in Heart Failure.
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DOI：
10.3389/fphys.2021.734210
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发表时间：
2021
影响因子：
4
通讯作者：
Gómez AM
中科院分区：
文献类型：
--
作者：
Benitah JP;Perrier R;Mercadier JJ;Pereira L;Gómez AM
心力衰竭（HF）被定义为心脏无法有效泵出足够的血液来维持身体的需要，首先是在运动时，然后是在休息时。Ca 2+处理的改变有助于衰竭心脏的收缩和舒张减少。虽然大多数Ca 2+处理蛋白的表达和/或功能已被证明是改变在许多模型的实验性HF，在这篇综述中，我们专注于肌浆网（SR）Ca 2+释放通道，2型兰尼碱受体（RyR 2）。已经报道了该通道的各种修饰诱导其功能的改变。第一个是RyR 2对通过L型钙通道的Ca 2+进入的激活反应较低的事实，这是心室心肌细胞超微结构重塑的功能结果，具有较少和混乱的横（T）小管。HF与升高的交感神经紧张和氧化环境有关。在这条线中，增强的RyR 2磷酸化和氧化已在人类和实验HF中显示。经过几次争论，现在普遍认为RyR 2在钙调蛋白激酶II位点（S2814）的磷酸化参与了衰竭心脏收缩功能的抑制和心肌敏感性的增强。FK 506结合蛋白FKBP12.6的表达减少也可能起作用。虽然这些改变主要是在射血分数降低的HF左心室中研究的，但最近的研究正在关注射血分数保留的HF。此外，HF中RyR 2的改变也可能导致与HF相关的室上性缺陷，如窦房结功能障碍和心房颤动。
Heart Failure (HF) is defined as the inability of the heart to efficiently pump out enough blood to maintain the body's needs, first at exercise and then also at rest. Alterations in Ca2+ handling contributes to the diminished contraction and relaxation of the failing heart. While most Ca2+ handling protein expression and/or function has been shown to be altered in many models of experimental HF, in this review, we focus in the sarcoplasmic reticulum (SR) Ca2+ release channel, the type 2 ryanodine receptor (RyR2). Various modifications of this channel inducing alterations in its function have been reported. The first was the fact that RyR2 is less responsive to activation by Ca2+ entry through the L-Type calcium channel, which is the functional result of an ultrastructural remodeling of the ventricular cardiomyocyte, with fewer and disorganized transverse (T) tubules. HF is associated with an elevated sympathetic tone and in an oxidant environment. In this line, enhanced RyR2 phosphorylation and oxidation have been shown in human and experimental HF. After several controversies, it is now generally accepted that phosphorylation of RyR2 at the Calmodulin Kinase II site (S2814) is involved in both the depressed contractile function and the enhanced arrhythmic susceptibility of the failing heart. Diminished expression of the FK506 binding protein, FKBP12.6, may also contribute. While these alterations have been mostly studied in the left ventricle of HF with reduced ejection fraction, recent studies are looking at HF with preserved ejection fraction. Moreover, alterations in the RyR2 in HF may also contribute to supraventricular defects associated with HF such as sinus node dysfunction and atrial fibrillation.
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