Oxidation of Ryanodine Receptors Promotes Ca 2+ Leakage and Contributes to Right Ventricular Dysfunction in Pulmonary Hypertension
| العنوان: | Oxidation of Ryanodine Receptors Promotes Ca 2+ Leakage and Contributes to Right Ventricular Dysfunction in Pulmonary Hypertension |
|---|---|
| المؤلفون: | Chuxiang Lei, Quan Fang, Yanru Wang, Su Yuan, Wenjun Xie, Ligang Fang, Xiaoying Yang, Yongfa Huang, Li Yan, Zhaojian Wang, Yan Zhao, Xiaohan Qin, Xiaoxiao Guo, Jing Wang |
| المصدر: | Hypertension. 77:59-71 |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, medicine.medical_specialty, Ryanodine receptor, business.industry, Diastole, Hemodynamics, 030204 cardiovascular system & hematology, medicine.disease, Ryanodine receptor 2, Pulmonary hypertension, Dantrolene, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Internal medicine, Heart failure, Internal Medicine, medicine, Cardiology, Decompensation, business, medicine.drug |
| الوصف: | 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 2+ 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 2+ leakage was detected along with reduced intracellular Ca 2+ transient amplitude and SR Ca 2+ 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 2+ 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 Ca 2+ leakage via oxidized RyR2 facilitates the development of RV failure. Dantrolene can inhibit diastolic SR Ca 2+ leakage in RV cardiomyocytes, delay right cardiac dysfunction, and improve the survival of rats with pulmonary arterial hypertension. |
| تدمد: | 1524-4563 0194-911X |
| DOI: | 10.1161/hypertensionaha.120.15561 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::ec5a31d6704bedbe1e5e0e6be2019b0a https://doi.org/10.1161/hypertensionaha.120.15561 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi...........ec5a31d6704bedbe1e5e0e6be2019b0a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15244563 0194911X |
|---|---|
| DOI: | 10.1161/hypertensionaha.120.15561 |