Oxidation of Ryanodine Receptors Promotes Ca2+ Leakage and Contributes to Right Ventricular Dysfunction in Pulmonary Hypertension
Oxidation of Ryanodine Receptors Promotes Ca2+ Leakage and Contributes to Right Ventricular Dysfunction in Pulmonary Hypertension
复制标题
Ryanodine 受体的氧化促进 Ca(2) 渗漏并导致肺动脉高压中的右心室功能障碍。
DOI：
10.1161/hypertensionaha.120.15561
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发表时间：
2021-01-01
期刊：
影响因子：
8.3
通讯作者：
Guo, Xiaoxiao
中科院分区：
文献类型：
--
作者：
Huang, Yongfa;Lei, Chuxiang;Guo, Xiaoxiao
右心室（RV）衰竭是肺动脉高压患者死亡的主要原因，其机制尚不清楚。虽然RyR2（ryanodine receptor type 2）在肌浆网（SR）上的功能障碍和心肌细胞中的异常Ca 2+循环在一些心血管疾病中已被认识到，但它们在继发于肺动脉高压的RV衰竭中的作用需要进一步研究。在野百合碱诱导的大鼠肺动脉高压模型中，根据血流动力学和形态学参数将RV重构过程分为正常、代偿和失代偿阶段。在代偿期和失代偿期，右室心肌细胞内钙瞬变幅度和SR钙含量均降低，舒张期SR钙渗漏明显，沿着减少。RyR2蛋白水平在此过程中逐渐下降，其巯基氧化比例在代偿期和失代偿期均高于正常期。二硫苏糖醇抑制RyR2氧化或丹曲林直接修复RyR2可恢复RV心肌细胞内Ca 2+稳态。每日腹腔注射丹曲林可延缓失代偿期进展，显著提高失代偿期肺动脉高压大鼠的存活率（79.3%vs55.9%，P =0.026）。我们的研究结果表明，舒张期SR Ca2+泄漏通过氧化RyR2促进RV衰竭的发展。丹曲林可抑制右室心肌细胞舒张期SR Ca2+漏出，延缓右心功能不全，改善肺动脉高压大鼠的生存。
Right ventricular (RV) failure is a major cause of death in patients with pulmonary arterial hypertension, and the mechanism of RV failure remains unclear. While the malfunction of RyR2 (ryanodine receptor type 2) on sarcoplasmic reticulum (SR) and aberrant Ca2+ cycling in cardiomyocytes have been recognized in some cardiovascular diseases, their roles in RV failure secondary to pulmonary arterial hypertension require further investigation. In a monocrotaline-induced rat model of pulmonary arterial hypertension, the RV remodeling process was divided into normal, compensated, and decompensated stages according to the hemodynamic and morphological parameters. In both compensated and decompensated stages, significant diastolic SR Ca2+ leakage was detected along with reduced intracellular Ca2+ transient amplitude and SR Ca2+ contents in RV myocytes. RyR2 protein levels decreased progressively during the process, and the thiol oxidation proportions of RyR2 were higher in compensated and decompensated stages than in normal stage. Inhibition of RyR2 oxidation by dithiothreitol or repairing RyR2 directly by dantrolene could restore Ca2+ homeostasis in RV myocytes. Daily intraperitoneal injection of dantrolene delayed decompensation progression and significantly improved the survival rate of pulmonary hypertension rats in decompensated stage (79.3% versus 55.9%; P=0.026). Our findings suggest that diastolic SR Ca2+ leakage via oxidized RyR2 facilitates the development of RV failure. Dantrolene can inhibit diastolic SR Ca2+ leakage in RV cardiomyocytes, delay right cardiac dysfunction, and improve the survival of rats with pulmonary arterial hypertension.