From the Department of Cardiology, Peking Union Medical College Hospital (Y.H., C.L., Z.W., X.Y., X.Q., Q.F., L.F., X.G.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Shaanxi, China (W.X.).
Hypertension. 2021 Jan;77(1):59-71. doi: 10.1161/HYPERTENSIONAHA.120.15561. Epub 2020 Nov 30.
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 Ca 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 Ca leakage was detected along with reduced intracellular Ca transient amplitude and SR Ca 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 Ca 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%; =0.026). Our findings suggest that diastolic SR Ca leakage via oxidized RyR2 facilitates the development of RV failure. Dantrolene can inhibit diastolic SR Ca leakage in RV cardiomyocytes, delay right cardiac dysfunction, and improve the survival of rats with pulmonary arterial hypertension.
右心室（RV）衰竭是肺动脉高压患者死亡的主要原因，而 RV 衰竭的机制仍不清楚。虽然肌浆网（SR）上 RyR2（兰尼碱受体 2）的功能障碍和心肌细胞中异常的 Ca 循环在一些心血管疾病中已得到公认，但它们在肺动脉高压引起的 RV 衰竭中的作用仍需进一步研究。在野百合碱诱导的肺动脉高压大鼠模型中，根据血流动力学和形态学参数，RV 重构过程分为正常、代偿和失代偿阶段。在代偿和失代偿阶段，均检测到明显的舒张期 SR Ca 渗漏，同时 RV 心肌细胞内 Ca 瞬变幅度和 SR Ca 含量减少。RyR2 蛋白水平在整个过程中逐渐下降，并且在代偿和失代偿阶段，RyR2 的巯基氧化比例高于正常阶段。二硫苏糖醇抑制 RyR2 氧化或直接用丹曲林修复 RyR2 均可恢复 RV 心肌细胞的 Ca 稳态。丹曲林每天腹腔注射可延迟失代偿期的进展，显著提高失代偿期肺动脉高压大鼠的存活率（79.3%比 55.9%；=0.026）。我们的研究结果表明，通过氧化 RyR2 导致的舒张期 SR Ca 渗漏促进 RV 衰竭的发展。丹曲林可抑制 RV 心肌细胞舒张期 SR Ca 渗漏，延迟右心功能障碍，并提高肺动脉高压大鼠的生存率。
