PKC-α regulates cardiac contractility and propensity toward heart failure
PKC-α regulates cardiac contractility and propensity toward heart failure
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DOI：
10.1038/nm1000
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发表时间：
2004-03-01
期刊：
影响因子：
82.9
通讯作者：
Molkentin, JD
中科院分区：
文献类型：
--
作者：
Braz, JC;Gregory, K;Molkentin, JD
蛋白激酶C(PKC)家族的丝氨酸/苏氨酸激酶在几乎所有膜相关信号转导通路的下游发挥作用。在这里，我们确定PKC-α是心肌细胞收缩能力和钙离子处理的基本调节因子。Prkca基因缺陷小鼠的心脏是高度收缩的，而过度表达Prkca的转基因小鼠的心脏是低收缩的。腺病毒基因转移显性阴性或野生型PKC-α进入心肌细胞分别增强或降低心肌细胞的收缩能力。从机制上讲，PKC活性的调节影响肌浆网钙ATPase-2(SERCA-2)泵抑制蛋白磷蛋白(PLB)的去磷酸化，改变肌浆网钙负荷和钙瞬变。PKC-直接磷酸化蛋白磷酸酶抑制物-1(I-1)，改变蛋白磷酸酶-1(PP-1)的活性，这可能是PKC-α对PLB磷酸化的影响的原因。Prkca缺失引起的高收缩能力可以预防压力超负荷引起的心力衰竭，以及通过缺失编码肌肉LIM蛋白的基因(Csrp3)而引起的扩张性心肌病。Prkca基因的缺失也挽救了与PP-1过度表达相关的心肌病。因此，PKC-α通过感知细胞内钙离子和信号转导事件，作为心脏收缩能力的节点积分器发挥作用，这可以深刻地影响心力衰竭的倾向。
The protein kinase C (PKC) family of serine/threonine kinases functions downstream of nearly all membrane- associated signal transduction pathways. Here we identify PKC-alpha as a fundamental regulator of cardiac contractility and Ca2+ handling in myocytes. Hearts of Prkca-deficient mice are hypercontractile, whereas those of transgenic mice overexpressing Prkca are hypocontractile. Adenoviral gene transfer of dominant-negative or wild-type PKC-alpha into cardiac myocytes enhances or reduces contractility, respectively. Mechanistically, modulation of PKC-activity affects dephosphorylation of the sarcoplasmic reticulum Ca2+ ATPase-2 (SERCA-2) pump inhibitory protein phospholamban (PLB), and alters sarcoplasmic reticulum Ca2+ loading and the Ca2+ transient. PKC-directly phosphorylates protein phosphatase inhibitor-1 (I-1), altering the activity of protein phosphatase-1 (PP-1), which may account for the effects of PKC-alpha on PLB phosphorylation. Hypercontractility caused by Prkca deletion protects against heart failure induced by pressure overload, and against dilated cardiomyopathy induced by deleting the gene encoding muscle LIM protein (Csrp3). Deletion of Prkca also rescues cardiomyopathy associated with overexpression of PP-1. Thus, PKC-alpha functions as a nodal integrator of cardiac contractility by sensing intracellular Ca2+ and signal transduction events, which can profoundly affect propensity toward heart failure.