Heart Failure-Related Hyperphosphorylation in the Cardiac Troponin I C Terminus Has Divergent Effects on Cardiac Function In Vivo.
Heart Failure-Related Hyperphosphorylation in the Cardiac Troponin I C Terminus Has Divergent Effects on Cardiac Function In Vivo.
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DOI：
10.1161/circheartfailure.117.003850
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发表时间：
2017-09
期刊：
影响因子：
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通讯作者：
Murphy AM
中科院分区：
文献类型：
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作者：
Li Y;Zhu G;Paolocci N;Zhang P;Takahashi C;Okumus N;Heravi A;Keceli G;Ramirez-Correa G;Kass DA;Murphy AM
在人类心力衰竭中，心肌肌钙蛋白I（cTnI）的Ser 199（相当于小鼠中的Ser 200）显著过度磷酸化，体外研究表明其增强肌丝钙敏感性并改变钙蛋白酶介导的cTnI蛋白水解。然而，其过度磷酸化如何影响体内心脏功能仍不清楚。为了解决这个问题，产生了两种转基因小鼠模型：磷酸模拟cTnIS 200 D和磷酸沉默cTnIS 200 A，每种都由心肌细胞特异性α-MHC启动子驱动。与同窝对照组相比，通过超声心动图和组织学评估的心脏结构在两种转基因模型中均正常（n=5）。基线体内血流动力学和离体肌肉研究显示，cTnIS 200 D显著延长舒张时间并降低左心室峰值充盈率，而射血分数和力量发展正常（n=5）。然而，随着心率增加或β-肾上腺素能刺激，cTnIS 200 D小鼠与对照组相比射血分数或力量发展增强较少，而舒张改善与对照组相似（n=5）。相比之下，cTnIS 200 A在基线和生理应激下功能正常。为了测试任一突变是否影响心脏对缺血应激的反应，使离体心脏经受缺血/再灌注。cTnIS 200 D受到保护，收缩功能恢复88±8%，而同窝对照组为35±15%，cTnIS 200 A为28±8%（n=5）。这与cTnIS 200 D心脏中cTnI蛋白水解较少相关。cTnI C端丝氨酸的过度磷酸化通过抑制基线舒张功能和限制生理应激下的收缩储备来影响心脏功能。然而，矛盾的是，它可能通过减少cTnI的蛋白水解来保护缺血/再灌注损伤后的心脏功能。
In human heart failure, Ser199 (equivalent to Ser200 in mouse) of cardiac troponin I (cTnI) is significantly hyper-phosphorylated and in vitro studies suggest it enhances myofilament calcium sensitivity and alters calpain-mediated cTnI proteolysis. However, how its hyper-phosphorylation affects cardiac function in vivo remains unknown. To address the question, two transgenic mouse models were generated: a phospho-mimetic cTnIS200D and a phospho-silenced cTnIS200A, each driven by the cardiomyocyte-specific α-MHC promoter. Cardiac structure assessed by echocardiography and histology were normal in both transgenic models compared to littermate controls (n=5). Baseline in vivo hemodynamics and isolated muscle studies showed that cTnIS200D significantly prolonged relaxation and lowered left ventricular peak filling rate, whereas ejection fraction and force development were normal (n=5). However, with increased heart rate or beta-adrenergic stimulation, cTnIS200D mice had less enhanced ejection fraction or force development versus controls, whereas relaxation improved similarly to controls (n=5). By contrast, cTnIS200A was functionally normal both at baseline and under the physiological stresses. To test if either mutation impacted cardiac response to ischemic stress, isolated hearts were subjected to ischemia/reperfusion. cTnIS200D were protected, recovering 88±8% of contractile function versus 35±15% in littermate controls and 28±8% in cTnIS200A (n=5). This was associated with less cTnI proteolysis in cTnIS200D hearts. Hyper-phosphorylation of this Serine in cTnI C-terminus impacts heart function by depressing diastolic function at baseline and limiting systolic reserve under physiological stresses. However, paradoxically it preserves heart function after ischemia/reperfusion injury potentially by decreasing proteolysis of cTnI.