Dashwood Alexander, Cheesman Elizabeth, Beard Nicole, Haqqani Haris, Wong Yee Weng, Molenaar Peter
Heart Lung Institute, The Prince Charles Hospital, Chermside, Brisbane, Queensland 4032, Australia.
Cardio-Vascular Molecular & Therapeutics Translational Research Group, Northside Clinical School of Medicine, Faculty of Medicine, University of Queensland, Brisbane, Queensland 4032, Australia.
ACS Pharmacol Transl Sci. 2020 Jun 1;3(4):563-582. doi: 10.1021/acsptsci.0c00003. eCollection 2020 Aug 14.
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 (Ca) is the ubiquitous secondary messenger of excitation-contraction coupling and provides a common pathway for contractile dysfunction and arrhythmia genesis. In a healthy heart, Ca 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 Ca leak. This increased cytosolic [Ca] promotes Ca extrusion via the local Na/Ca 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/Ca cycling proteins, result in pathological Ca 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.
心力衰竭（HF）是一种全球性的流行病，具有显著的死亡率和发病率。尽管有目前的药物治疗，但50%的患者在诊断后5年内死亡。在这些死亡病例中，30%-50%将是由室性心律失常导致的心脏性猝死。本综述讨论了两种应激诱导机制，即慢性β-肾上腺素能受体（β-AR）刺激引起的磷酸化和氧化应激引起的硫醇修饰，以及它们如何调节心脏2型兰尼碱受体（RyR2）并促进致心律失常表型。钙（Ca）是兴奋-收缩偶联中普遍存在的第二信使，为收缩功能障碍和心律失常的发生提供了一条共同途径。在健康心脏中，Ca由RyR2从肌浆网（SR）释放。RyR2的开放概率受到协同蛋白、离子和激酶的动态影响，它们处于严格平衡状态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激诱导机制，使RyR2的控制解偶联，导致病理性舒张期SR钙泄漏。这种细胞溶质[Ca]的增加促进了通过局部钠/钙交换器的钙外流，导致肌膜净去极化、延迟后去极化和室性心律失常。研究氧化应激和磷酸化的实验模型旨在确定对RyR2大分子复合物以及相关钠/钙循环蛋白的翻译后修饰如何导致病理性钙处理和舒张期泄漏。然而，致病的分子变化仍存在争议且未明确。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治疗靶点。
