Heart failure (HF) is a global pandemic with significant mortality and morbidity. Despite current medications, 50% of individuals die within 5 years of diagnosis. Of these deaths, 30–50% will be a result of sudden cardiac death from ventricular arrhythmias. This review discusses two stress-induced mechanisms, phosphorylation from chronic β-adrenoceptor (β-AR) stimulation and thiol modifications from oxidative stress, and how they modulate the cardiac ryanodine receptor type 2 (RyR2) and foster an arrhythmogenic phenotype. Calcium (Ca²⁺) is the ubiquitous secondary messenger of excitation–contraction coupling and provides a common pathway for contractile dysfunction and arrhythmia genesis. In a healthy heart, Ca²⁺ is released from the sarcoplasmic reticulum (SR) by RyR2. The open probability of RyR2 is under the dynamic influence of co-proteins, ions, and kinases that are in strict balance to ensure normal physiological functioning. In HF, chronic β-AR activity and production of reactive oxygen species and reactive nitrogen species provide two stress-induced mechanisms uncoupling RyR2 control, resulting in pathological diastolic SR Ca²⁺ leak. This increased cytosolic [Ca²⁺] promotes Ca²⁺ extrusion via the local Na⁺/Ca²⁺ exchanger, resulting in net sarcolemmal depolarization, delayed after depolarization and ventricular arrhythmia. Experimental models researching oxidative stress and phosphorylation have aimed to identify how post-translational modifications to the RyR2 macromolecular complex, and the associated Na⁺/Ca²⁺ cycling proteins, result in pathological Ca²⁺ handling and diastolic leak. However, the causative molecular changes remain controversial and undefined. Through understanding the molecular mechanisms that produce an arrhythmic phenotype, novel therapeutic targets to treat HF and prevent its malignant course can be identified.

中文翻译：

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了解磷酸化和氧化还原修饰如何调节心脏Ryanodine受体2型活性，以在晚期心力衰竭中产生心律失常的表型。

心力衰竭（HF）是全球性大流行，死亡率和发病率均很高。尽管有目前的药物治疗，仍有50％的人在诊断后5年内死亡。在这些死亡中，有30％至50％是由于室性心律不齐而导致的心源性猝死。这篇综述讨论了两种压力诱导的机制，即慢性β-肾上腺素能受体（β-AR）刺激的磷酸化和氧化应激的硫醇修饰，以及它们如何调节2型心脏ryanodine受体（RyR2）并促进心律失常的表型。钙（Ca ²⁺）是无处不在的刺激－收缩耦合的次要信使，它为收缩功能障碍和心律失常的发生提供了一条通用途径。在健康的心脏中，Ca ²⁺通过RyR2从肌质网（SR）释放。RyR2的开放可能性受共蛋白质，离子和激酶的动态影响，这些蛋白质必须严格平衡以确保正常的生理功能。在HF中，慢性β-AR活性以及活性氧和活性氮的产生提供了两种应力诱导的机制，从而使RyR2控制脱钩，导致病理性舒张性SR Ca ²⁺泄漏。这种增加的胞质[Ca ²⁺ ]通过局部Na ⁺ / Ca ²⁺促进Ca ^2+的挤出交换，导致净肌膜去极化，去极化后延迟和室性心律失常。研究氧化应激和磷酸化的实验模型旨在确定RyR2大分子复合物以及相关的Na ⁺ / Ca ²⁺循环蛋白的翻译后修饰如何导致病理性Ca ²⁺处理和舒张期渗漏。然而，致病分子的变化仍然是有争议的且不确定的。通过了解产生心律失常表型的分子机制，可以确定治疗HF并预防其恶性病程的新型治疗靶标。