Cho M C, Rapacciuolo A, Koch W J, Kobayashi Y, Jones L R, Rockman H A
Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
J Biol Chem. 1999 Aug 6;274(32):22251-6. doi: 10.1074/jbc.274.32.22251.
Calsequestrin is a high capacity Ca(2+)-binding protein in the junctional sarcoplasmic reticulum that forms a quaternary complex with junctin, triadin, and the ryanodine receptor. Transgenic mice with cardiac-targeted calsequestrin overexpression show marked suppression of Ca(2+)-induced Ca(2+) release, myocyte hypertrophy, and premature death by 16 weeks of age (Jones, L. R., Suzuki, Y. J., Wang, W., Kobayashi, Y. M., Ramesh, V., Franzini-Armstrong, C., Cleemann, L., and Morad, M. (1998) J. Clin. Invest. 101, 1385-1393). To investigate whether alterations in intracellular Ca(2+) trigger changes in the beta-adrenergic receptor pathway, we studied calsequestrin overexpressing transgenic mice at 7 and 14 weeks of age. As assessed by echocardiography, calsequestrin mice at 7 weeks showed mild left ventricular enlargement, mild decreased fractional shortening with increased wall thickness. By 14 weeks, the phenotype progressed to marked left ventricular enlargement and severely depressed systolic function. Cardiac catheterization in calsequestrin mice revealed markedly impaired beta-adrenergic receptor responsiveness in both 7- and 14- week mice. Biochemical analysis in 7- and 14-week mice showed a significant decrease in total beta-adrenergic receptor density, adenylyl cyclase activity, and the percent high affinity agonist binding, which was associated with increased beta-adrenergic receptor kinase 1 levels. Taken together, these data indicate that alterations in beta-adrenergic receptor signaling precede the development of overt heart failure in this mouse model of progressive cardiomyopathy.
肌集钙蛋白是连接肌质网中一种高容量的Ca(2+)结合蛋白，它与连接蛋白、三联蛋白和雷诺丁受体形成四级复合物。心脏靶向性过表达肌集钙蛋白的转基因小鼠在16周龄时表现出Ca(2+)诱导的Ca(2+)释放、心肌细胞肥大和过早死亡受到显著抑制（琼斯，L.R.，铃木，Y.J.，王，W.，小林，Y.M.，拉梅什，V.，弗兰齐尼-阿姆斯特朗，C.，克莱曼，L.，和莫拉德，M.（1998年）《临床研究杂志》101，1385 - 1393）。为了研究细胞内Ca(2+)的改变是否会引发β-肾上腺素能受体途径的变化，我们研究了7周龄和14周龄的过表达肌集钙蛋白的转基因小鼠。通过超声心动图评估，7周龄的肌集钙蛋白小鼠表现出轻度左心室扩大，轻度缩短分数降低且壁厚增加。到14周时，表型进展为显著的左心室扩大和严重的收缩功能抑制。对肌集钙蛋白小鼠进行心脏导管插入术显示，7周龄和14周龄的小鼠β-肾上腺素能受体反应性均明显受损。对7周龄和14周龄小鼠的生化分析显示，总β-肾上腺素能受体密度、腺苷酸环化酶活性和高亲和力激动剂结合百分比显著降低，这与β-肾上腺素能受体激酶1水平升高有关。综上所述，这些数据表明，在这种进行性心肌病小鼠模型中，β-肾上腺素能受体信号传导的改变先于明显心力衰竭的发生。
