Sildenafil ameliorates left ventricular T-tubule remodeling in a pressure overload-induced murine heart failure model
Sildenafil ameliorates left ventricular T-tubule remodeling in a pressure overload-induced murine heart failure model
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DOI：
10.1038/aps.2016.13
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发表时间：
2016-04-01
影响因子：
8.2
通讯作者：
Song, Long-sheng
中科院分区：
文献类型：
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作者：
Huang, Chun-kai;Chen, Bi-yi;Song, Long-sheng
目的：西地那非是一种磷酸二酯酶5 （PDE5）抑制剂，已被证明对心力衰竭有有益作用。本研究的目的是测试西地那非是否抑制左心室（LV）衰竭时的横小管（t小管）重构，从而提供治疗益处。方法：采用胸主动脉束带法（TAB）建立小鼠压力超负荷心力衰竭模型。TAB后1天给予小鼠西地那非100 mg.kg（-1）。D (-1), sc)或生理盐水5周。治疗结束时，超声心动图检查左室功能。然后解剖完整心脏，置于langendorff灌注室，原位共聚焦成像心外膜肌细胞t小管超微结构。结果：TAB手术导致心力衰竭，并伴有明显的t小管重构。西地那非治疗可显著减轻tab诱导的心肌肥厚和充血性心力衰竭，改善左室收缩功能，保持左室心肌细胞t小管完整性。但西地那非治疗对心室扩张无显著影响。左室t小管结构完整性与心肌肥厚（R-2= 0.74， P< 0.01）和左室整体功能（R-2= 0.47， P< 0.01）相关。结论：西地那非可有效改善TAB小鼠左室t小管重构，揭示了西地那非治疗心力衰竭的新机制。
Aim: Sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, has been shown to exert beneficial effects in heart failure. The purpose of this study was to test whether sildenafil suppressed transverse-tubule (T-tubule) remodeling in left ventricular (LV) failure and thereby providing the therapeutic benefits.Methods: A pressure overload-induced murine heart failure model was established in mice by thoracic aortic banding (TAB). One day after TAB, the mice received sildenafil (100 mg.kg(-1). d(-1), sc) or saline for 5 weeks. At the end of treatment, echocardiography was used to examine LV function. Then the intact hearts were dissected out and placed in Langendorff-perfusion chamber for in situ confocal imaging of T-tubule ultrastructure from epicardial myocytes.Results: TAB surgery resulted in heart failure accompanied by remarkable T-tubule remodeling. Sildenafil treatment significantly attenuated TAB-induced cardiac hypertrophy and congestive heart failure, improved LV contractile function, and preserved T-tubule integrity in LV cardiomyocytes. But sildenafil treatment did not significantly affect the chamber dilation. The integrity of LV T-tubule structure was correlated with cardiac hypertrophy (R-2= 0.74, P< 0.01) and global LV function (R-2= 0.47, P< 0.01).Conclusion: Sildenafil effectively ameliorates LV T-tubule remodeling in TAB mice, revealing a novel mechanism underlying the therapeutic benefits of sildenafil in heart failure.