Long-term simulated microgravity causes cardiac RyR2 phosphorylation and arrhythmias in mice

INTERNATIONAL JOURNAL OF CARDIOLOGY

卷:176

Article

Respress, Jonathan L.^1,2  Gershovich, Pavel M.²  Wang, Tiannan²  Reynolds, Julia O.²  Skapura, Darlene G.²  Sutton, Jeffrey P.^1,4  Miyake, Christina Y.^1,2,5  Wehrens, Xander H. T.^1,2,3,4 

[1] Baylor Coll Med, Cardiovasc Res Inst, Houston, TX 77030 USA

[2] Baylor Coll Med, Dept Mol Physiol & Biophys, Houston, TX 77030 USA

[3] Baylor Coll Med, Dept Med Cardiol, Houston, TX 77030 USA

[4] Baylor Coll Med, Natl Space Biomed Res Inst, Ctr Space Med, Houston, TX 77030 USA

[5] Texas Childrens Hosp, Dept Pediat Cardiol, Houston, TX 77030 USA

关键词: Arrhythmia;    Calcium;    Ca/calmodulin-dependent kinase II;    Microgravity;    Ryanodine receptor;   

DOI  :  10.1016/j.ijcard.2014.08.138

来源: Elsevier

【 摘 要 】

Background: Long-term exposure to microgravity during space flight may lead to cardiac remodeling and rhythm disturbances. In mice, hindlimb unloading (HU) mimics the effects of microgravity and stimulates physiological adaptations, including cardiovascular deconditioning. Recent studies have demonstrated an important role played by changes in intracellular Ca handling in the pathogenesis of heart failure and arrhythmia. In this study, we tested the hypothesis that cardiac remodeling following HU in mice involves abnormal intracellular Ca regulation through the cardiac ryanodine receptor (RyR2). Methods and results: Mice were subjected to HU by tail suspension for 28 to 56 days in order to induce cardiac remodeling (n = 15). Control mice (n = 19) were treated equally, with the exception of tail suspension. Echocardiography revealed cardiac enlargement and depressed contractility starting at 28 days post-HU versus control. Moreover, mice were more susceptible to pacing-induced ventricular arrhythmias after HU. Ventricular myocytes isolated from HU mice exhibited an increased frequency of spontaneous sarcoplasmic reticulum (SR) Ca release events and enhanced SR Ca leak via RyR2. Western blotting revealed increased RyR2 phosphorylation at S2814, and increased CaMKII auto-phosphorylation at T287, suggesting that CaMKII activation of RyR2 might underlie enhanced SR Ca release in HU mice. Conclusion: These data suggest that abnormal intracellular Ca handling, likely due to increased CaMKII phosphorylation of RyR2, plays a role in cardiac remodeling following simulated microgravity in mice. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

【 授权许可】

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