Cardiac myosin binding protein-C phosphorylation in a {beta}-myosin heavy chain background.
Cardiac myosin binding protein-C phosphorylation in a {beta}-myosin heavy chain background.
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DOI：
10.1161/circulationaha.108.798983
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发表时间：
2009-03-10
期刊：
影响因子：
37.8
通讯作者：
Robbins J
中科院分区：
文献类型：
--
作者：
Sadayappan S;Gulick J;Klevitsky R;Lorenz JN;Sargent M;Molkentin JD;Robbins J
心肌肌球蛋白结合蛋白-C（cMyBP-C）磷酸化调节心肌收缩力。当在cMyBP-C null（cMyBP-C（t/t））心脏中表达时，cMyBP-C磷酸化模拟物（cMyBP-CAIP+）拯救心脏功能障碍并保护心脏免受缺血-再灌注（I/R）损伤。然而，cMyBP-C功能可能依赖于肌球蛋白亚型。由于这些替换是在主要含有α-肌球蛋白重链（α-MyHC）的小鼠心脏中进行的，因此数据对心肌细胞主要含有β-MyHC的人类的适用性尚不清楚。我们确定了cMyBP-C磷酸化在“人源化”小鼠心脏中的作用，其中>80%的α-MyHC被β-MyHC取代，β-MyHC是人类心肌中主要的肌球蛋白同种型。为了确定在β-MyHC背景下cMyBP-C磷酸化的影响，将表达正常cMyBP-C（cMyBP-CWT）、不可磷酸化的cMyBP-C（cMyBP-CAIIP-）或cMyBP-CAIIP+的转基因小鼠繁殖到β-MyHC背景（β）中。然后将这些小鼠与cMyBP-C（t/t）背景杂交，以确保不存在内源性cMyBP-C。cMyBP-C（t/t）/β和cMyBP-CAlIP-：（t/t）/β小鼠由于心力衰竭而过早死亡，证实cMyBP-C磷酸化在β-MyHC背景中是必需的。cMyBP-CAlIP+：（t/t）/β和cMyBP-CWT：（t/t）/β心脏未显示发病率和死亡率，并且cMyBP-CAlIP+：（t/t）/β心脏被显著保护免于I/R损伤。cMyBP-C磷酸化对于β-MyHC背景下的基础心肌功能是必需的，并且可以在I/R损伤后保持功能。我们的研究证明了cMyBP-C磷酸化作为人类心脏治疗靶点的探索。
Cardiac myosin binding protein-C (cMyBP-C) phosphorylation modulates cardiac contractility. When expressed in cMyBP-C null (cMyBP-C(t/t)) hearts, a cMyBP-C phosphomimetic (cMyBP-CAllP+), rescued cardiac dysfunction and protected the hearts from ischemic-reperfusion (I/R) injury. However, cMyBP-C function may be dependent upon the myosin isoform type. Since these replacements were carried out in the mouse heart, which contains predominantly α-myosin heavy chain (α-MyHC), the applicability of the data to the human, whose cardiomyocytes contain predominantly β-MyHC, is unclear. We determined the effect(s) of cMyBP-C phosphorylation in a “humanized” mouse heart in which >80% of the α-MyHC was replaced by β-MyHC, which is the predominant myosin isoform in human cardiac muscle. To determine the effects of cMyBP-C phosphorylation in a β-MyHC background, transgenic mice expressing normal cMyBP-C (cMyBP-CWT), nonphosphorylatable cMyBP-C (cMyBP-CAllP-), or cMyBP-CAllP+ were bred into the β-MyHC background (β). These mice were then crossed into the cMyBP-C(t/t) background to ensure the absence of endogenous cMyBP-C. cMyBP-C(t/t)/β and cMyBP-CAllP-:(t/t)/β mice died prematurely due to heart failure, confirming that cMyBP-C phosphorylation is essential in the β-MyHC background. cMyBP-CAllP+:(t/t)/β and cMyBP-CWT:(t/t)/β hearts showed no morbidity and mortality and cMyBP-CAllP+:(t/t)/β hearts were significantly cardioprotected from I/R injury. cMyBP-C phosphorylation is necessary for basal myocardial function in the β-MyHC background and can preserve function after I/R injury. Our studies justify exploration of cMyBP-C phosphorylation as a therapeutic target in the human heart.