Response by El Refaey et al to Letter Regarding Article, "Protein Phosphatase 2A Regulates Cardiac Na+ Channels".
Response by El Refaey et al to Letter Regarding Article, "Protein Phosphatase 2A Regulates Cardiac Na+ Channels".
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El Refaey 等人对有关文章“蛋白磷酸酶 2A 调节心脏 Na 通道”的信件的回复。
DOI：
10.1161/circresaha.119.314938
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发表时间：
2019
影响因子：
20.1
通讯作者：
Mohler,PeterJ
中科院分区：
文献类型：
--
作者：
ElRefaey,Mona;Musa,Hassan;Smith,SakimaA;Binkley,PhilipF;Bradley,Elisa;Hund,ThomasJ;Mohler,PeterJ
心血管疾病是导致死亡的主要原因，预计到2030年将导致超过2300万人死亡。在这些死亡中，每年有150万人将经历疟疾引起的心源性猝死。1因此，研究新的策略，以减轻肾上腺素能失衡与肾上腺素生成是必不可少的公共卫生。在心脏中，尽管初级电压门控Nav通道Nav 1. 5，对于正常的心脏兴奋性是至关重要的，INa的晚期成分（INa，L）的改变与遗传性和获得性心律失常有关。我们的团队和其他人已经确定了Nav 1的CaMK II依赖性磷酸化。5作为心肌细胞、心血管疾病动物模型和人类心脏中致病性INa，L增加的重要驱动因素。我们最近发表的新发现支持PP 2A（蛋白磷酸酶2A）在调节心脏致病性INa，L中的关键作用。2 PP 2A是一种广泛表达的丝氨酸/苏氨酸磷酸酶，在心脏中高表达。虽然蛋白磷酸酶1是心脏中的主要PP，但PP 2A活性调节关键膜蛋白的活性。PP 2A全酶由3个亚基（支架[A]、调节[B]和催化[C]）组成。PP 2A A/C亚基由2个基因编码，而13个不同的基因编码PP 2A调节亚基。我们的研究结果支持缺乏特定调节亚基（B56α）的小鼠在Nav 1中显示改变。5 CaMKII依赖性磷酸化（减少），并最终降低INa，L对异丙肾上腺素的反应。2尽管这些发现支持B56α在INa，L调节中的意想不到的作用，但这项工作对潜在的分子机制提出了质疑。例如，B56α的缺失可能导致Nav 1表达的缺陷。5调节复合物。此外，先前的结构工作已经支持，在不存在调节亚基的情况下，PP 2A A/C全酶虽然调节较少，但显示出增加的活性。3此外，调节亚基与催化亚基比例的改变可增加PP 2A活性。4 B56α的缺失可能影响其他调节亚基以及上游和下游调节分子的活性。最后，由于我们的研究使用的是所有组织中缺乏B56α的小鼠，继发性非心脏机制可能有助于表型。总之，这项工作为未来的研究提供了一个理论基础，以了解PP 2A和INa，L之间的联系，特别是考虑到INa，L在人类中的致癌作用。我们感谢Cristóbal等人的评论，强调了PP 2A调控（和潜在的PP 2A为基础的治疗）的全球影响。与他们的评论相关的是，继发于化疗药物的心脏肿瘤并发症的发生是综合护理团队面临的一个重大挑战。心血管疾病是癌症幸存者的头号死因，因此我们必须关注心血管功能和癌症治疗之间的相互作用。
Cardiovascular disease is a leading cause of death and is expected to account for> 23 million deaths by 2030. Of those deaths, one-half million each year will experience arrhythmia-induced sudden cardiac death. 1 Therefore, research on new strategies to mitigate adrenergic imbalance associated with arrhythmogenesis is essential to public health. In the heart, although the activity of the primary voltage-gated Nav channel, Nav1. 5, is critical for normal cardiac excitability, alteration of the late component of INa (INa, L) is linked with heritable and acquired arrhythmias. Our group and others have identified CaMKII-dependent phosphorylation of Nav1. 5 as an important driver of increased pathogenic INa, L in myocyte, animal models of cardiovascular disease, and human heart. We recently published new findings that support a critical role for PP2A (protein phosphatase 2A) in the regulation of pathogenic INa, L in heart. 2 PP2A is a ubiquitously expressed serine/threonine phosphatase with high expression in the heart. Although protein phosphatase 1 is the dominant PP in heart, PP2A activity regulates the activity of key membrane proteins. The PP2A holoenzyme comprised of 3 subunits (scaffolding [A], regulatory [B], and catalytic [C]). PP2A A/C subunits are encoded by 2 genes, whereas thirteen different genes encode PP2A regulatory subunits. Our findings support that mice lacking a specific regulatory subunit (B56α) display alteration in Nav1. 5 CaMKII-dependent phosphorylation (reduced) and ultimately decreased INa, L in response to isoproterenol. 2 Although the findings support an unanticipated role for B56α in INa, L regulation, the work raises questions about the underlying molecular mechanism. For example, loss of B56α may lead to defects in the expression of Nav1. 5 regulatory complex in the myocyte. Further, prior structural work has supported that in the absence of the regulatory subunit, the PP2A A/C holoenzyme, while less regulated, displays increased activity. 3 In addition, alterations in the ratio of regulatory subunit: catalytic subunit may increase PP2A activity. 4 Loss of B56α may impact the activity of other regulatory subunits as well as up-and downstream regulatory molecules. Finally, as our work used mice lacking B56α in all tissue, secondary noncardiac mechanisms may contribute to phenotypes. In summary, the work provides a rationale for future studies to understand the link between PP2A and INa, L, particularly given the arrhythmogenic role for INa, L in humans.We appreciate the comments from Cristóbal et al highlighting the global impact of PP2A regulation (and potential PP2A-based therapies). Relevant to their comments, the occurrence of cardio-oncological complications secondary to antineoplastic agents represents a major challenge to comprehensive care teams. Cardiovascular disease is the number one cause of death in cancer survivors, 5, 6 and so it is imperative that we focus on the interaction between cardiovascular function and cancer therapies.