A Sarcoplasmic Reticulum Localized Protein Phosphatase Regulates Phospholamban Phosphorylation and Promotes Ischemia Reperfusion Injury in the Heart.
A Sarcoplasmic Reticulum Localized Protein Phosphatase Regulates Phospholamban Phosphorylation and Promotes Ischemia Reperfusion Injury in the Heart.
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DOI：
10.1016/j.jacbts.2016.12.002
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发表时间：
2017-03
期刊：
影响因子：
--
通讯作者：
Ruan H
中科院分区：
文献类型：
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作者：
Akaike T;Du N;Lu G;Minamisawa S;Wang Y;Ruan H
PP2Ce 是特异性定位于 SR 并在心肌细胞中表达的 Ser-Thr 磷酸酶。 PP2Ce 具有特异性磷酸酶活性，可使受磷蛋白的 Thr-17 位点去磷酸化。 PP2Ce 表达是在病理应激（包括 β-AR 刺激和 ROS）下诱导的。 PP2Ce 诱导抑制心肌细胞钙循环，降低 β-AR 诱导的收缩力，并促进氧化缺血/再灌注损伤。 PP2Ce 是应激介导的心肌细胞钙调节的新分子成分。 Phospholamban (PLN) 是心肌细胞肌膜钙摄取的关键调节因子；其对肌膜内质网钙ATP酶的抑制活性受磷酸化调节。 PLN 低磷酸化是衰竭心脏的常见分子特征。目前的研究在分子、细胞和全心脏水平上提供了证据，表明肌膜膜靶向蛋白磷酸酶 PP2Ce 是一种特异性且有效的 PLN 磷酸酶。 PP2Ce 表达在衰竭的人类心脏中升高，并通过心肌细胞中的 β-肾上腺素能刺激或氧化应激在蛋白质水平上急性诱导。小鼠心脏中的 PP2Ce 表达减弱了 β-肾上腺素能反应并加剧了缺血/再灌注损伤。因此，PP2Ce是心脏功能和发病机制的新调节剂。
PP2Ce is Ser-Thr phosphatase specifically localized on SR and expressed in cardiomyocytes. PP2Ce has specific phosphatase activity to dephosphorylate Thr-17 site of phospholamban. PP2Ce expression is induced upon pathological stress, including beta-AR stimulation and ROS. PP2Ce induction suppresses cardiomyocyte calcium cycling, reduces beta-AR-induced contractility, and promotes oxidative ischemia/reperfusion injury. PP2Ce is a new molecular component of stress-mediated cardiomyocyte calcium regulation. Phospholamban (PLN) is a key regulator of sarcolemma calcium uptake in cardiomyocyte; its inhibitory activity to sarcolemma-endoplasmic reticulum calcium ATPase is regulated by phosphorylation. PLN hypophosphorylation is a common molecular feature in the failing heart. The current study provided evidence at the molecular, cellular, and whole-heart levels to implicate a sarcolemma membrane-targeted protein phosphatase, PP2Ce, as a specific and potent PLN phosphatase. PP2Ce expression was elevated in failing human heart and induced acutely at protein level by β-adrenergic stimulation or oxidative stress in cardiomyocytes. PP2Ce expression in mouse heart blunted β-adrenergic response and exacerbated ischemia/reperfusion injury. Therefore, PP2Ce is a new regulator for cardiac function and pathogenesis.