Proteolytic N-terminal truncation of cardiac troponin I enhances ventricular diastolic function
Proteolytic N-terminal truncation of cardiac troponin I enhances ventricular diastolic function
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DOI：
10.1074/jbc.m408525200
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发表时间：
2005-02-25
影响因子：
4.8
通讯作者：
Jin, JP
中科院分区：
文献类型：
--
作者：
Barbato, JC;Huang, QQ;Jin, JP
除了所有肌钙蛋白I亚型中保守的核心结构外，心脏肌钙蛋白I （cTnI）还有一个n端延伸，该延伸包含β -肾上腺素能调节下蛋白激酶A的磷酸化位点。正常心肌中n端调控结构域的限制性切割发生，并在血流动力学适应过程中上调。Yu L.-F。张和j.p。金（2001）。化学，276,15753-15760)。在本研究中，我们建立了在心脏中过表达n端截断cTnI （cTnI- nd）的转基因小鼠，以研究其生化和生理意义。Ca2+激活的肌动球蛋白atp酶活性表明，cTnI-ND肌原纤维对Ca2+的亲和力低于对照组，类似于异丙肾上腺素治疗的效果。体内和离体工作心脏实验显示，与对照组相比，cTnI-ND心脏的舒张速度明显加快，左室舒张末期压明显降低。cTnI-ND心脏较高的基线松弛率与野生型小鼠心脏在β -肾上腺素能刺激下的水平相似。与对照组相比，cTnI-ND心脏因预负荷降低而导致的心输出量减少明显较小。这些发现表明，通过限制性蛋白水解去除cTnI的n端延伸，通过增加心肌舒张率和降低左室舒张末期压来促进心室充盈，从而增强心功能，从而更好地利用Frank-Starling机制。
Besides the core structure conserved in all troponin I isoforms, cardiac troponin I (cTnI) has an N-terminal extension that contains phosphorylation sites for protein kinase A under beta-adrenergic regulation. A restricted cleavage of this N-terminal regulatory domain occurs in normal cardiac muscle and is up-regulated during hemodynamic adaptation (Z.-B. Yu, L.-F. Zhang, and J.-P. Jin (2001) J. Biol. Chem. 276, 15753-15760). In the present study, we developed transgenic mice overexpressing the N-terminal truncated cTnI (cTnI-ND) in the heart to examine its biochemical and physiological significance. Ca2+-activated actomyosin ATPase activity showed that cTnI-ND myofibrils had lower affinity for Ca2+ than controls, similar to the effect of isoproterenol treatment. In vivo and isolated working heart experiments revealed that cTnI-ND hearts had a significantly faster rate of relaxation and lower left ventricular end diastolic pressure compared with controls. The higher baseline relaxation rate of cTnI-ND hearts was at a level similar to that of wild type mouse hearts under beta-adrenergic stimulation. The decrease in cardiac output due to lowered preload was significantly smaller for cTnI-ND hearts compared with controls. These findings indicate that removal of the N-terminal extension of cTnI via restricted proteolysis enhances cardiac function by increasing the rate of myocardial relaxation and lowering left ventricular end diastolic pressure to facilitate ventricular filling, thus resulting in better utilization of the Frank-Starling mechanism.