Catecholaminergic polymorphic ventricular tachycardia (CPVT) is associated with mutations in the cardiac ryanodine receptor (RyR2). These result in stress‐induced ventricular arrhythmic episodes, with clinical symptoms and prognosis reported more severe in male than female patients. Murine homozygotic RyR2‐P2328S (RyR2S/S) hearts replicate the proarrhythmic CPVT phenotype of abnormal sarcoplasmic reticular Ca2+ leak and disrupted Ca2+ homeostasis. In addition, RyR2S/S hearts show decreased myocardial action potential conduction velocities (CV), all features implicated in arrhythmic trigger and substrate. The present studies explored for independent and interacting effects of RyR2S/S genotype and sex on expression levels of molecular determinants of Ca2+ homeostasis (CASQ2, FKBP12, SERCA2a, NCX1, and CaV1.2) and CV (NaV1.5, Connexin (Cx)‐43, phosphorylated‐Cx43, and TGF‐β1) in mice. Expression levels of Ca2+ homeostasis proteins were not altered, hence implicating abnormal RyR2 function alone in disrupted cytosolic Ca2+ homeostasis. Furthermore, altered NaV1.5, phosphorylated Cx43, and TGF‐β1 expression were not implicated in the development of slowed CV. By contrast, decreased Cx43 expression correlated with slowed CV, in female, but not male, RyR2S/S mice. The CV changes may reflect acute actions of the increased cytosolic Ca2+ on NaV1.5 and Cx43 function.

中文翻译：

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模拟儿茶酚胺能多形性室性心动过速的小鼠心室中的蛋白质表达谱：基因型和性别的影响

儿茶酚胺能多形性室性心动过速 (CPVT) 与心脏兰尼碱受体 (RyR2) 的突变有关。这些导致压力诱发的室性心律失常发作，据报道男性患者的临床症状和预后比女性患者更严重。小鼠纯合子 RyR2-P2328S (RyR2S/S) 心脏复制了异常肌浆网状 Ca2+ 泄漏和破坏 Ca2+ 稳态的促心律失常 CPVT 表型。此外，RyR2S/S 心脏显示心肌动作电位传导速度 (CV) 降低，所有特征都与心律失常触发和底物有关。本研究探讨了 RyR2S/S 基因型和性别对 Ca2+ 稳态（CASQ2、FKBP12、SERCA2a、NCX1 和 CaV1.2）和 CV（NaV1.5、Connexin (Cx) 的分子决定因素表达水平的独立和相互作用影响） ‐43, 小鼠中的磷酸化 Cx43 和 TGF-β1。Ca2+ 稳态蛋白的表达水平没有改变，因此暗示 RyR2 功能异常单独导致细胞溶质 Ca2+ 稳态被破坏。此外，改变的 NaV1.5、磷酸化的 Cx43 和 TGF-β1 表达与减缓的 CV 的发展无关。相比之下，在雌性而非雄性 RyR2S/S 小鼠中，Cx43 表达降低与 CV 减慢相关。CV 变化可能反映了增加的胞质 Ca2+ 对 NaV1.5 和 Cx43 功能的急性作用。在雌性而非雄性 RyR2S/S 小鼠中，Cx43 表达降低与 CV 减慢相关。CV 变化可能反映了增加的胞质 Ca2+ 对 NaV1.5 和 Cx43 功能的急性作用。在雌性而非雄性 RyR2S/S 小鼠中，Cx43 表达降低与 CV 减慢相关。CV 变化可能反映了增加的胞质 Ca2+ 对 NaV1.5 和 Cx43 功能的急性作用。