Wang Lei, Zhang Shijie, Zou Cao, Liu Zhihua
Department of Cardiology, First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, People's Republic of China.
Chin J Physiol. 2011 Apr 30;54(2):133-42. doi: 10.4077/cjp.2011.amm070.
Diastolic heart failure (DHF) and systolic heart failure (SHF) are two clinical subsets of chronic heart failure (CHF). Sarcoplasmic reticulum (SR) Ca²⁺ leak has been measured in SHF and might contribute to contractile dysfunction and arrhythmogenesis. However, no study has investigated a similar phenomenon in DHF. Thus, we established DHF and SHF rabbit models and compared the differences in Ca²⁺ leak between these models. New Zealand white rabbits were randomly divided into three groups (n = 8 in each group): sham operation (SO) group, DHF group and SHF group. Cardiac functions were determined by echocardiography and hemodynamic assays. The SR Ca²⁺ leak was measured with a calcium-imaging device and the expression and activities of related proteins were evaluated with Western blots and autophosphorylation. In the DHF group, there was significantly increased ventricular wall thickness and stiffness, reduced diastolic function, and total amount of FK506 binding protein 12.6 (FKBP12.6), increased expression and activity of protein kinase A (PKA) and phosphorylation site (P2809) in the ryanodine receptor (RyR2), but no prominent Ca²⁺ leak. In the SHF group, there was significantly increased ventricular cavity size, reduced systolic function, increased SR Ca²⁺ leak, reduced total amount of FKBP12.6 and FKBP12.6-RyR2 association, increased expression and activity of PKA and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) and their RyR2 phosphorylation sites with unchanged P2030. Our results suggest that a prominent SR Ca²⁺ leak was not observed in the DHF model, which may provide a new idea for the reasons in preserved systolic function, and CaMKII possibly plays a more important role in SR Ca²⁺ leak.
舒张性心力衰竭（DHF）和收缩性心力衰竭（SHF）是慢性心力衰竭（CHF）的两个临床亚型。已在SHF中检测到肌浆网（SR）Ca²⁺泄漏，其可能导致收缩功能障碍和心律失常的发生。然而，尚无研究在DHF中探究类似现象。因此，我们建立DHF和SHF兔模型，并比较这些模型之间Ca²⁺泄漏的差异。将新西兰白兔随机分为三组（每组n = 8）：假手术（SO）组、DHF组和SHF组。通过超声心动图和血流动力学测定来确定心功能。用钙成像设备测量SR Ca²⁺泄漏，并用蛋白质印迹法和自磷酸化评估相关蛋白的表达和活性。在DHF组中，心室壁厚度和僵硬度显著增加，舒张功能降低，FK506结合蛋白12.6（FKBP12.6）总量减少，蛋白激酶A（PKA）的表达和活性以及兰尼碱受体（RyR2）中的磷酸化位点（P2809）增加，但没有明显的Ca²⁺泄漏。在SHF组中，心室腔大小显著增加，收缩功能降低，SR Ca²⁺泄漏增加，FKBP12.6总量和FKBP12.6 - RyR2结合减少，PKA和Ca²⁺/钙调蛋白依赖性蛋白激酶II（CaMKII）的表达和活性及其RyR2磷酸化位点增加，而P2030不变。我们的结果表明，在DHF模型中未观察到明显的SR Ca²⁺泄漏，这可能为收缩功能保留的原因提供新的思路，并且CaMKII可能在SR Ca²⁺泄漏中起更重要的作用。
