UCR1C is a novel activator of phosphodiesterase 4 (PDE4) long isoforms and attenuates cardiomyocyte hypertrophy.
UCR1C is a novel activator of phosphodiesterase 4 (PDE4) long isoforms and attenuates cardiomyocyte hypertrophy.
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DOI：
10.1016/j.cellsig.2015.02.003
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发表时间：
2015-05
影响因子：
4.8
通讯作者：
Carnegie GK
中科院分区：
文献类型：
--
作者：
Wang L;Burmeister BT;Johnson KR;Baillie GS;Karginov AV;Skidgel RA;O'Bryan JP;Carnegie GK
肥大会增加心力衰竭和心律失常的风险。因此，已经提出预防或逆转适应不良的肥大表型来治疗心力衰竭。慢性β-肾上腺素能受体（β-AR）刺激通过升高3′，5′-环磷酸腺苷（cAMP）水平并激活下游效应物如蛋白激酶A（PKA）诱导心肌细胞肥大。相反，磷酸二酯酶（PDE）对cAMP的水解在时空上限制cAMP信号传导。在这里，我们证明，PDE 4，而不是PDE 3，是在调节心肌细胞肥大的关键，并可能代表一个潜在的目标，以防止适应不良肥大。我们确定了PDE 4D上游保守区1内的序列，称为UCR 1C，作为PDE 4长亚型的新型激活剂。UCR 1C激活与A-激酶锚定蛋白（AKAP）-Lbc复合的PDE 4，导致AKAP-Lbc促进的PKA信号传导减少。UCR 1C在心肌细胞中的表达抑制对慢性β-AR刺激的响应的肥大。这种效应部分是由于抑制核PKA活性，从而降低了转录因子cAMP反应元件结合蛋白（CREB）的磷酸化。总之，UCR 1C激活PDE 4通过特异性抑制核PKA活性来减弱心肌细胞肥大。
Hypertrophy increases the risk of heart failure and arrhythmia. Prevention or reversal of the maladaptive hypertrophic phenotype has thus been proposed to treat heart failure. Chronic β-adrenergic receptor (β-AR) stimulation induces cardiomyocyte hypertrophy by elevating 3′, 5′-cyclic adenosine monophosphate (cAMP) levels and activating downstream effectors such protein kinase A (PKA). Conversely, hydrolysis of cAMP by phosphodiesterases (PDEs) spatiotemporally restricts cAMP signaling. Here, we demonstrate that PDE4, but not PDE3, is critical in regulating cardiomyocyte hypertrophy, and may represent a potential target for preventing maladaptive hypertrophy. We identify a sequence within the upstream conserved region 1 of PDE4D, termed UCR1C, as a novel activator of PDE4 long isoforms. UCR1C activates PDE4 in complex with A-Kinase anchoring protein (AKAP)-Lbc resulting in decreased PKA signaling facilitated by AKAP-Lbc. Expression of UCR1C in cardiomyocytes inhibits hypertrophy in response to chronic β-AR stimulation. This effect is partially due to inhibition of nuclear PKA activity, which decreases phosphorylation of the transcription factor cAMP response element-binding protein (CREB). In conclusion, PDE4 activation by UCR1C attenuates cardiomyocyte hypertrophy by specifically inhibiting nuclear PKA activity.
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影响因子：
4.6
作者：
Carnegie, Graeme K.;Means, Christopher K.;Scott, John D.
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影响因子：
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