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Physiological and pathological Roles of the CD38/cyclic ADP-ribose signal system in cardiac myocytes

CD38/环ADP-核糖信号系统在心肌细胞中的生理和病理作用

基本信息

批准号：
12470032
负责人：
TAKASAWA Shin
金额：
$ 8.9万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

CD38 catalyzes both the formation and hydrolysis of cyclic ADP-ribose (cADPR). To elucidate whether the CD38/cADPR signaling system plays a significant role in Ca^<2+> cycling in vivo, we analyzed the myocardium of CD38 knockout mice (CD38KO).In CD38KO, the myocardial cADPR content was reduced by 85% compared with wild-type mice (WT), and cardiac hypertrophy developed only in males but not in females. At physiological temperature (36.1±0.2℃), none of the parameters for Ca^<2+> transients and forces of papillary muscles differed between WT and CD38KO. In contrast, at lower temperature (26.8±0.2℃), at which the effects of cADPR are supposed to be lost, the peak [Ca^<2+>]I was significantly increased and the time constant of decline in [Ca^<2+>]I and minimum of the first derivative of force were significantly decreased in both-gender CD38KO compared with gender-matched WT. Additionally, in female CD38KO, the maximum of the first derivative of force was significantly increased. Western blot analysis revealed that, in both-gender CD38KO, the expression levels of sarcoplasmic reticulum Ca^<2+> ATPase type 2 (SERCA2) and the SERCA2-to-phospholamban ratio were significantly increased compared with WT. The ryanodine receptor protein level was significantly increased in female CD38KO, but not in male CD38KO, compared with gender-matched WT.These data suggest the CD38/cADPR signaling system plays an important role in intracellular Ca2+ homeostasis in cardiac myocytes in vivo. Its deficiency was compensated differentially according to gender, which might be responsible at least partially for the different hypertrophic responses between genders.

CD 38催化环状ADP-核糖（cADPR）的形成和水解。为了阐明CD 38/cADPR信号系统是否在体内Ca^<2+>循环中起重要作用，我们分析了CD 38敲除小鼠（CD 38 KO）的心肌，结果发现，与野生型小鼠（WT）相比，CD 38 KO小鼠的心肌cADPR含量降低了85%，并且仅在雄性小鼠中出现心肌肥大，而在雌性小鼠中没有。在生理温度（36.1±0.2℃）下，WT和CD 38 KO之间的Ca^<2+>瞬变和乳头肌力参数无差异。相反，在较低的温度（26.8±0.2℃）下，与性别匹配的WT相比，在cADPR的作用被认为丧失的温度下，两性CD 38 KO的[Ca^2+]I峰值显著增加，[Ca^2+]I下降的时间常数和力的一阶导数的最小值显著降低。此外，在雌性CD 38 KO中，力的一阶导数的最大值显著增加。Western blot分析显示，与WT相比，在两性CD 38 KO中，肌浆网Ca^2+ ATP酶2（SERCA 2）的表达水平和SERCA 2与受磷蛋白的比率显著增加。Ryanodine受体蛋白水平在女性CD 38 KO中显著增加，但在男性CD 38 KO中没有。这些数据表明，CD 38/cADPR信号系统在体内心肌细胞内Ca 2+稳态中起着重要作用。它的不足根据性别差异补偿，这可能是负责至少部分的性别之间的不同肥大反应。