Regulation of cardiac stress signaling by protein kinase D1
Regulation of cardiac stress signaling by protein kinase D1
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DOI：
10.1128/mcb.26.10.3875-3888.2006
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发表时间：
2006-05-01
影响因子：
5.3
通讯作者：
McKinsey, Timothy A.
中科院分区：
文献类型：
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作者：
Harrison, Brooke C.;Kim, Mi-Sung;McKinsey, Timothy A.
作为对诸如高血压或心肌梗死等病理性应激的反应，心脏经历了与心肌细胞肥大、心肌细胞死亡和纤维化相关的重塑过程。组蛋白去乙酰基酶5(HDAC5)是一种心脏重构的转录抑制因子，在应激信号的反应中，依赖于磷酸化的中和作用。最近的研究表明，蛋白激酶C(PKC)及其下游效应蛋白激酶D_1(PKD_1)在控制HDAC5的磷酸化中起着重要作用。虽然PKCs是心脏信号的调节者，但PKD1在心肌中的功能仍不清楚。在这里，我们证明了不同的肥大激动剂通过G蛋白偶联受体(GPCRs)和Rho GTP酶发出信号来刺激心肌细胞中PKD1的催化活性。心肌细胞中PKD1的激活是通过PKC依赖和非依赖的机制实现的。在体内，在多种病理性心脏重塑的啮齿动物模型中，心脏PKD1被激活。PKD1的激活与依赖磷酸化的HDAC5核输出相关，通过小干扰RNA降低内源性PKD1的表达可抑制HDAC5的穿梭和相关的心肌细胞生长。相反，在小鼠心脏中异位过度表达固有活性的PKD1会导致扩张型心肌病。这些发现支持PKD1通过其磷酸化和中和HDAC5的能力在控制心脏病理性重塑中的作用。
In response to pathological stresses such as hypertension or myocardial infarction, the heart undergoes a remodeling process that is associated with myocyte hypertrophy, myocyte death, and fibrosis. Histone deacetylase 5 (HDAC5) is a transcriptional repressor of cardiac remodeling that is subject to phosphorylation-dependent neutralization in response to stress signaling. Recent studies have suggested a role for protein kinase C (PKC) and its downstream effector, protein kinase D1 (PKD1), in the control of HDAC5 phosphorylation. While PKCs are well-documented regulators of cardiac signaling, the function of PKD1 in heart muscle remains unclear. Here, we demonstrate that PKD1 catalytic activity is stimulated in cardiac rnyocytes by diverse hypertrophic agonists that signal through G protein-coupled receptors (GPCRs) and Rho GTPases. PKD1 activation in cardiomyocytes occurs through PKC-dependent and -independent mechanisms. In vivo, cardiac PKD1 is activated in multiple rodent models of pathological cardiac remodeling. PKD1 activation correlates with phosphorylation-dependent nuclear export of HDAC5, and reduction of endogenous PKD1 expression with small interfering RNA suppresses HDAC5 shuttling and associated cardiomyocyte growth. Conversely, ectopic overexpression of constitutively active PKD1 in mouse heart leads to dilated cardiomyopathy. These findings support a role for PKD1 in the control of pathological remodeling of the heart via its ability to pbosphorylate and neutralize HDAC5.