Abstract：
Ca2+ transients (CaT) underlying cardiomyocyte (CM) contraction require efficient Ca2+ coupling between sarcolemmal Ca2+ channels and sarcoplasmic reticulum (SR) ryanodine receptor Ca2+ channels (RyR) for their generation; reduced coupling in disease contributes to diminished CaT and arrhythmogenic Ca2+ events. SR Ca2+ release also occurs via inositol 1,4,5-trisphosphate receptors (InsP3R) in CM. While this pathway contributes negligeably to Ca2+ handling in healthy CM, rodent studies support a role in altered Ca2+ dynamics and arrhythmogenic Ca2+ release involving InsP3R crosstalk with RyRs in disease. Whether this mechanism persists in larger mammals with lower T-tubular density and coupling of RyRs is not fully resolved. We have recently shown an arrhythmogenic action of InsP3-induced Ca2+ release (IICR) in end stage human heart failure (HF), often associated with underlying ischemic heart disease (IHD). How IICR contributes to early stages of disease is however not determined but highly relevant. To access this stage, we chose a porcine model of IHD, which shows substantial remodelling of the area adjacent to the infarct. In cells from this region, IICR preferentially augmented Ca2+ release from non-coupled RyR clusters that otherwise showed delayed activation during the CaT. IICR in turn synchronised Ca2+ release during the CaT but also induced arrhythmogenic delayed afterdepolarizations and action potentials. Nanoscale imaging identified co-clustering of InsP3Rs and RyRs, thereby allowing Ca2+-mediated channel crosstalk. Mathematical modelling supported and further delineated this mechanism of enhanced InsP3R-RyRs coupling in MI. Our findings highlight the role of InsP3R-RyR channel crosstalk in Ca2+ release and arrhythmia during post-MI remodelling.
摘要：
心肌细胞（CM）收缩背后的Ca2瞬变（CaT）需要肌膜Ca2通道和肌浆网（SR）ryanodine受体Ca2通道（RyR）之间的有效Ca2偶联才能产生；疾病中耦合减少有助于减少CaT和致心律失常性Ca2事件。SRCa2释放也通过CM中的肌醇1,4,5-三磷酸受体（InsP3R）发生。虽然这种途径对健康CM中的Ca2+处理贡献可忽略不计，啮齿动物研究支持在改变的Ca2动力学和心律失常性Ca2释放中的作用，涉及InsP3R与RyRs的串扰。这种机制是否在具有较低T管密度和RyRs偶联的较大哺乳动物中持续存在尚未完全解决。我们最近显示了InsP3诱导的Ca2释放（IICR）在终末期人类心力衰竭（HF）中的心律失常作用，常与原发性缺血性心脏病（IHD）相关。然而，IICR如何影响疾病的早期阶段尚未确定，但高度相关。要进入这个阶段，我们选择了猪IHD模型,这显示了与梗塞相邻的区域的实质性重塑。在这个区域的细胞中，IICR优先增加了非偶联RyR簇的Ca2释放，否则在CaT过程中显示出延迟的激活。IICR反过来使CaT期间的Ca2释放同步，但也诱导了心律失常性延迟的后去极化和动作电位。纳米级成像确定了InsP3Rs和RyRs的共聚簇，从而允许Ca2+介导的通道串扰。数学建模支持并进一步描述了MI中InsP3R-RyRs增强偶联的机制。我们的发现强调了InsP3R-RyR通道串扰在MI后重塑过程中Ca2释放和心律失常中的作用。
