CaMKII-dependent myofilament Ca2+ desensitization contributes to the frequency-dependent acceleration of relaxation.
CaMKII-dependent myofilament Ca2+ desensitization contributes to the frequency-dependent acceleration of relaxation.
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DOI：
10.1016/j.ceca.2015.08.001
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发表时间：
2015-11
期刊：
影响因子：
4
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Guilbert A;Lim HJ;Cheng J;Wang Y
先前的研究表明，CaMK II活性是心室肌细胞频率依赖性舒张加速（FDAR）所必需的。我们提出，潜在的机制涉及CaMKII依赖性调节肌丝Ca2+的敏感性。采用小鼠心脏超声仪测定小鼠心功能。[Ca2用IonOptixCa2+图像分析系统测量肌节长度。将起搏频率从0.5 Hz增加到4Hz，可诱导左心室肌细胞频率依赖性肌丝钙脱敏（FDMCD）和FDAR。PKA或PKC的急性抑制没有效果，而CaMKII抑制废除FDMCD和FDAR。已检测到CaMKII和肌钙蛋白I（TnI）的免疫共沉淀，并且CaMKII抑制显著降低了TnI的丝氨酸残基磷酸化。最后，体内慢性抑制CaMKII降低了TnI磷酸化，并消除了FDAR和FDMCD，导致舒张功能受损。我们的研究结果表明，CaMKII依赖的TnI磷酸化参与FDMCD和随之而来的FDAR和CaMKII抑制消除这种机制，从而诱导舒张功能障碍。
Previous studies suggest that CaMKII activity is required for frequency-dependent acceleration of relaxation (FDAR) in ventricular myocytes. We propose that the underlying mechanism involves CaMKII-dependent regulation of myofilament Ca2+ sensitivity. Cardiac function was measured in mice using murine echo machine. [Ca2+]i and sarcomere length were measured by IonOptix Ca2+ image system. Increasing pacing rate from 0.5 to 4Hz in left ventricular myocytes induced frequency-dependent myofilament Ca2+ desensitization (FDMCD) and FDAR. Acute inhibition of PKA or PKC had no effect, whereas CaMKII inhibition abolished both FDMCD and FDAR. Co-immunoprecipitation of CaMKII and troponin I (TnI) has been detected and CaMKII inhibition significantly reduced serine residue phosphorylation of TnI. Finally, chronic inhibition of CaMKII in vivo reduced TnI phosphorylation and abolished both FDAR and FDMCD, leading to impaired diastolic function. Our results suggest that CaMKII-dependent TnI phosphorylation is involved in FDMCD and the consequent FDAR and that CaMKII inhibition removes this mechanism and thus induces diastolic dysfunction.