Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling
Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling
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DOI：
10.1096/fj.05-3744fje
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发表时间：
2005-12
期刊：
影响因子：
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通讯作者：
Toshihiro Takeda;M. Asahi;O. Yamaguchi;S. Hikoso;H. Nakayama;Y. Kusakari;M. Kawai;K. Hongo;
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文献类型：
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作者：
Toshihiro Takeda;M. Asahi;O. Yamaguchi;S. Hikoso;H. Nakayama;Y. Kusakari;M. Kawai;K. Hongo;
家族性阿尔茨海默病家族的遗传学研究表明，早老素2(PS2)与该疾病的发病机制有关。PS2在包括心脏在内的各种组织中普遍表达。在这项研究中，我们检测了PS2基因敲除(PS2KO)小鼠的心脏表型，以阐明PS2在心脏中的作用。PS2KO小鼠发育正常，无心肌肥大和纤维化迹象。有创血流动力学分析显示，PS2KO组小鼠的心肌收缩能力高于其仔鼠对照组。对分离的乳头肌的研究表明，PS2KO小鼠的钙瞬变峰值和峰值张力显著高于其仔鼠对照组。PS2KO小鼠心脏钙调节蛋白表达无明显变化。既然已经证明大脑中的PS2与作为心脏Ryanodine受体(RyR2)调节剂的索尔辛相互作用，我们测试了PS2是否也与RyR2相互作用。免疫沉淀分析表明，PS2、Sorin和RyR2在过度表达这些蛋白的HEK-293细胞中或在小鼠心脏中相互作用。心肌免疫组织化学显示PS2与RyR2和Sorin共定位于Z线。升高的钙离子减弱了RyR2与PS2的联系，而山梨素与PS2的联系则增强了。PS2KO小鼠在低细胞外[Ca~(2+)]时可观察到钙瞬变和收缩能力增强，但在高[Ca~(2+)]时未观察到。综上所述，我们的结果提示PS2通过与RyR2相互作用在心脏兴奋-收缩偶联中发挥重要作用。
Genetic studies of families with familial Alzheimer's disease have implicated presenilin 2 (PS2) in the pathogenesis of this disease. PS2 is ubiquitously expressed in various tissues including hearts. In this study, we examined cardiac phenotypes of PS2 knockout (PS2KO) mice to elucidate a role of PS2 in hearts. PS2KO mice developed normally with no evidence of cardiac hypertrophy and fibrosis. Invasive hemodynamic analysis revealed that cardiac contractility in PS2KO mice increased compared with that in their littermate controls. A study of isolated papillary muscle showed that peak amplitudes of Ca2+ transients and peak tension were significantly higher in PS2KO mice than those in their littermate controls. PS2KO mouse hearts exhibited no change in expression of calcium regulatory proteins. Since it has been demonstrated that PS2 in brain interacts with sorcin, which serves as a modulator of cardiac ryanodine receptor (RyR2), we tested whether PS2 also interacts with RyR2. Immmunoprecipitation analysis showed that PS2, sorcin, and RyR2 interact with each other in HEK‐293 cells overexpressing these proteins or in mouse hearts. Immunohistochemistry of heart muscle indicated that PS2 colocalizes with RyR2 and sorcin at the Z‐lines. Elevated Ca2+ attenuated the association of RyR2 with PS2, whereas the association of sorcin with PS2 was enhanced. The enhanced Ca2+ transients and contractility in PS2KO mice were observed at low extracellular [Ca2+] but not at high levels of [Ca2+]. Taken together, our results suggest that PS2 plays an important role in cardiac excitation‐contraction coupling by interacting with RyR2.